Neuroprotective disruption of kv2.1/syntaxin interaction by small molecules

ABSTRACT

Disclosed herein are small molecule compounds capable of disrupting Kv2.1-syntaxin binding. The compounds are useful for treating a variety of neurological disorders, diseases, and injuries.

CROSS-REFERENCE TO RELATED APPLICATION

This application claims the benefit of U.S. Provisional Applications62/712,514, filed on Jul. 31, 2018, and 62/716,734, filed Aug. 9, 2018,the contents of each are hereby incorporated in its entirety.

STATEMENT OF GOVERNMENT SUPPORT

This invention was made with government support under NS043277 andGM097082 awarded by the National Institutes of Health. The governmenthas certain rights in the invention.

FIELD OF THE INVENTION

The invention is directed to compounds that modulate intracellularpotassium concentrations, and to the use of such compounds for thetreatment of neurological injuries and diseases.

BACKGROUND

A critical convergent factor in cell death programs is the modulation ofintracellular K⁺, which, at normal, physiological concentrations,suppresses the activation of several proteases and nucleases linked tocellular injury (Hughes Jr & Cidlowski, 1999). Indeed, enhanced K⁺efflux following injurious stimuli can rapidly deplete intracellular K⁺,thereby enabling the completion of cell death cascades (Yu et al., 1997;Yu, 2003). This K⁺ outflow is mediated by the delayed rectifierpotassium channel Kv2.1 in several neuronal subtypes, including corticalneurons (Pal et al., 2003), hippocampal pyramidal neurons (Chi & Xu,2000; Wu et al., 2015), midbrain dopaminergic neurons (Redman et al.,2006), and cerebellar granule cells (Jiao et al., 2007). Upstream ofKv2.1-facilitated cell death programs, oxidative and nitrosative stressaccompanying most forms of acute or chronic neuronal injury liberateintracellular zinc from metal binding proteins. This rise in zincinitiates an enzymatic cascade leading to the sequential phosphorylationof Kv2.1 residues Y124 and S800 by Src and p38 kinases, respectively(Redman et al., 2007; Redman et al., 2009; He et al., 2015). This dualphosphorylation of the channel enhances its interaction with the SNAREprotein syntaxin 1A (syntaxin), leading to increased surface expressionof active Kv2.1 and the subsequent intracellular K⁺ loss (Pal et al,2003; Pal et al, 2006; Redman et al, 2006; McCord & Aizenman, 2013; Shah& Aizenman, 2014). This series of events appear to be exclusivelyassociated with cell death processes and thereby represent a promisingtarget for novel neuroprotective strategies (McCord et al, 2014; Yeh etal, 2017).

The domain within Kv2.1 responsible for its interaction with syntaxin islocated within the Kv2.1 proximal cytosolic c-terminal, termed C1a(Singer-Lahat et al., 2007). Overexpression of a protein fragmentcontaining residues 441-522 within the C1a (Kv2.1 rat sequence;accession #NP_037318.1) is sufficient to inhibit the injury-inducedplasma membrane insertion of Kv2.1 channels in neurons and provideneuroprotection in vitro (McCord et al, 2014). More recently, ourlaboratory narrowed down the amino acid sequence within C1a to 9residues, HLSPNKWKW (C1aB; from N- to C-terminus, corresponding to Kv2.1residues 478-486 in rat, and 482-490 in mouse and humans (Accession #sNP_032446.2 and NP_004966.1, respectively). The conjugation of thissequence to a cell-permeant domain yielded a blood brainbarrier-permeable peptide (TAT-C1aB) that effectively ameliorated acuteneuronal injury in vivo (Yeh et al., 2017).

Although TAT-C1aB represents an intriguing therapeutic candidate,peptide-based therapeutics possess several innate disadvantages,including poor pharmacokinetic properties and metabolic instability.Thus, there remains a need for improved Kv2.1-syntaxin bindingdisrupters.

SUMMARY

Disclosed herein are small molecule Kv2.1-syntaxin binding disrupters.

The details of one or more embodiments are set forth in the descriptionsbelow. Other features, objects, and advantages will be apparent from thedescription and from the claims.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 depicts representative molecular dynamics snapshots of fourKv2.1-derived peptides labelled with their respective binding strength.From first row down, Kv2.1 peptides containing: sequence up to thesecond KW motif, sequence up to the K of the second KW motif, sequenceinclusive of the entire C1aB, natural Kv2.1 residues of the region.

FIG. 2 depicts first KW motif from 100 snapshots of the correspondingpeptides every 4 ns (after 100 ns of equilibration), snapshots werealigned on the W (grey). Strong binding peptides have W solvent exposedand ready to make contact with interacting surface, this is disrupted inpeptides of the first two rows with compromised second KW motif.

FIG. 3 depicts the binding region of syntaxin (teal surface) and munc-18(green surface) from PDB 3C98. Zoom region of munc-18 N-terminal motif25-31 interaction with syntaxin, stacking of munc-18 W28 and syntaxinF34 is shown. Note that this peptide is only a very small, peripheralcomponent of the full binding interface of munc-18 and syntaxin.

FIG. 4 depicts far-western assay of the C1aB sequence with sequentialalanine substitutions, one residue at a time. Tryptophan toalanine-substituted peptides had significantly less syntaxin bindingthan the parent peptide (*p<0.05; ANOVA/Dunnett). Results indicatemean±SEM of signal intensity in 4 independent assays.

FIG. 5 depicts docked C1aB peptide and cpd5 recapitulates interactionsof munc18/syntaxin co-crystal. Closed form of syntaxin from munc18co-crystal (PDB 4JEH) is shown in green and cyan (surface/sticks)corresponding to the Habc and the H3 domains, respectively. Syntaxin F34is shown in magenta to emphasize specific aromatic stacking interactionin all panels. a, Partial view of munc18/syntaxin co-crystal. Orangesticks show same munc18 peptide as in FIG. 1c , other munc18 residuesmaking favorable interactions are shown in yellow sticks. Red spherehighlights fully coordinated crystal water. b, Unbiased docking model ofC1aB/syntaxin. c, Docking model of cpd5/syntaxin. Water molecule isshown as a guide-to-the-eye to highlight the overlap with the ureamoeity of cpd5. d, Highlighted intermolecular interactions ofmunc18/syntaxin that are recapitulated in e, detailed view ofinteractions between docked pose of C1aB and syntaxin. Specifically,munc18 W28 aromatic stacking is mimicked by C1aB W7; hydrophobicinteractions between munc18 I57 and T56 and syntaxin I115 are mirroredby C1aB W9 (blue shade); hydrogen bond between munc18 T48 and syntaxinD231 is reproduced by FU in C1aB (red shade), f, Interactions betweencpd5 and syntaxin. Namely, benzothiazole ring forms stacking interactionwith F34, with urea moeity fully recapitulating hydrogen bonds formed bycrystal water in munc18 (red sphere). Syntaxin is identical in ah thestructures with the exception of Q119 and T122 sidechains inC1aB/syntaxin, which, in the absence of the crystal water, rotateslightly to satisfy its hydrogen bonds and methyl group interactions.

FIG. 6 depicts representative figures of the neuronal culture treatedwith TBOA, with and without cpd5 pre- and coincubation. Phase-brightcells represent neurons. Scale bar denotes 100 μm.

FIG. 7 depicts incubation of cortical culture neurons with 10 μM cpd5was found to be highly neuroprotective against 75 μM TBOA-inducedexcitotoxicity. This protective effect was comparable with its peptidecounterpart, TAT-C1aB (1 μM). (Vehicle vs cpd5 vs TAT-C1aB relativetoxicity mean±SEM: 3.70±0.33 vs 1.84±0.42 vs 1.89±0.15; *p<0.05;Kruskal-Wallis non-parametric ANOVA; n=3-8).

FIG. 8 depicts current density traces (top) and plots of the evokeddelayed rectifier currents at +30 mV. The 50 μM TBOA-evoked increase indelayed rectifier current was significantly suppressed by the presenceof 10 μM cpd5 (DMSO vs TBOA vs cpd5+TBOA: 85.92±13.53 vs 139.28±9.05 vs100.12±,9.61 pA/pF; One-way ANOVA/Dunnett, *p<0.05). Scale bar indicates100 pA/pF and 50 ms; n=10-12.

FIG. 9 depicts cpd5 (10 μM) did not inhibit NMDA-induced Ca²⁺ responsesin cultured cortical neurons (% Control±SEM, F-peak treated 101.26±1.47,AUC treated 104.67±1.98, n=4, 160 cells, *p>0.05; t-test). Responsesshown are the average of 40 Fura-2 loaded cells in 2 separatecoverslips. Four coverslips were utilized for our analysis.

FIG. 10 depicts Far-Western assay of the proximal Kv2.1 C-terminus (C1a)region using 15 a. a. segments spanning residues Kv2.1 451-540, inoverlapping 1 a. a. steps. Bar graph shows the summary (n=4) of syntaxinbinding intensity in the presence of 100 μM cpd5 or 0.1% DMSO as vehiclecontrol. The C1a binding sequence is highlighted in red.

FIG. 11 depicts Concentration-dependent effect of cpd5 on syntaxinbinding to the peptides 22-28 (containing the full C1aB19 domain) of thepeptide array. Percent inhibition of syntaxin binding compared to 0.1%DMSO is plotted for various concentrations of cpd5. The data were fittedin GraphPad Prism with a log (inhibitor) vs normalized response withvariable slope curve, which yielded an IC50 of 5.5 μM. *p<0.05,non-parametric Mann-Whitney for each peptide.

FIG. 12 depicts A graphical summary of coimmunoprecipitation experimentsusing HEK293 cells transfected with munc18 and syntaxin in the presenceof 10, 30, or 100 μM cpd5. Cells incubated in either 30 or 100 μM cpd5showed a significant displacement of munc18 from syntaxin. Cpd5 at theconcentration that we have observed neuroprotection (10 μM) did notdisplace munc18 from syntaxin. One representative blot from eachconcentration is presented above. (From 10 to 100 μM: 1.032±0.034,0.4459±0.09367, 0.4339±0.135, cpd5/DMSO mean±SEM; *p<0.05, Tukey'smultiple comparisons, n=3 each).

FIG. 13 depicts Left: Schematic of stereotaxic injections for labelingof corticocollicular and corticocallosal neurons with differentflourospheres to identify select neurons in the auditory cortex foracute slice electrophysiology (left panel). The right panel depictsschematic illustrating slice electrophysiology experiment involvingelectrical stimulation of auditory cortex layer 2/3 while recording fromadjacent labeled corticocallosal neurons.

FIG. 14 depicts Representative traces of a layer 2/3 corticocallosalneuron AMPAR EPSCs evoked by electrical stimulation of adjacent layer2/3 sites while incubated in control (black) and in 10 μM cpd5 (red).

FIG. 15 depicts the time course of the average amplitude of AMPAR EPSCsbefore and after cpd5 treatment.

FIG. 16 depicts the average effect of cpd5 (red) on layer 2/3corticocallosal neuron AMPAR EPSCs amplitudes, normalized to control(control vs. cpd5: 97.6±0.9%, p=0.153, paired t-test, n=4 cells from 4mice).

FIG. 17 depicts the chemical structure of certain tested compounds.

FIG. 18 depicts the LDH toxicity assay screening of four small moleculesevaluated for innate toxicity to primary rat cortical neuron cultures.

FIG. 19 depicts the LDH toxicity assay screening of the lead compoundcpd5 in primary cortical neuron cultures found no innate toxicity of upto 30 μM for 24 hr.

FIG. 20 depicts the incubation of cortical culture neurons with 10 μMcpd3, cpd4, or cpd6 provided no neuroprotection against 75 μMTBOA-induced excitoxicity (Vehicle vs cpd3 vs cpd4 vs cpd6 relativetoxicity mean±SEM: 2.99±0.32 vs 2.75±0.72 vs 3.48±1.1 vs 3.12±0.65;Kruskal-Wallis non-parametric ANOVA; n=3-9).

FIG. 21 Top: Confirmation that the 68 kDa band to be munc18 and the 33kDa band to be syntaxin 1A by observing that they do not appear insamples without prior transfection with appropriate plasmids in HEKcells. The munc18 antibody does not detect the syntaxin band. In thefirst blot, munc18 was probed first, followed by syntaxin. Bottom: In aseparate run of the same sample, the specificity of the syntaxinantibody was confirmed by probing with the syntaxin antibody only,observing relatively lack of signal at the MW for munc18. Theco-transfection of munc18 with syntaxin appears to induce a formation ofa higher molecular weight syntaxin species. Bands at 50 and 25 kDa arethe heavy and light chain of the pulldown antibody, respectively.

FIG. 22 depicts Schematic illustrating slice electrophysiologyexperiment evaluating the intrinsic properties of L5B corticocollicularneurons after retrograde labeling.

FIG. 23 depicts an evaluation of subthreshold intrinsic properties founda lack of significant effect of cpd5 incubation on resting membranepotential.

FIG. 24 depicts an evaluation of subthreshold intrinsic properties founda lack of significant effect of cpd5 incubation on input resistance.

FIG. 25 depicts an evaluation of subthreshold intrinsic properties founda lack of significant effect of cpd5 incubation on sag ratio (V₂/V₁).

FIG. 26 depicts An evaluation of evoked properties also found nosignificant effect of cpd5 incubation on action potential threshold.Available representative traces are provided for each experiment. Eachneuron is evaluated before and after 10 min incubation in 10 μM cpd5(Paired t-test; for firing rates, 2-way ANOVA; n=4 cells from 4 mice).

FIG. 27 depicts An evaluation of evoked properties also found nosignificant effect of cpd5 incubation on width. Available representativetraces are provided for each experiment. Each neuron is evaluated beforeand after 10 min incubation in 10 μM cpd5 (Paired t-test; for firingrates, 2-way ANOVA; n=4 cells from 4 mice).

FIG. 28 depicts An evaluation of evoked properties also found nosignificant effect of cpd5 incubation on firing rate. Availablerepresentative traces are provided for each experiment. Each neuron isevaluated before and after 10 min incubation in 10 μM cpd5 (Pairedt-test; for firing rates, 2-way ANOVA; n=4 cells from 4 mice).

DETAILED DESCRIPTION

Before the present methods and systems are disclosed and described, itis to be understood that the methods and systems are not limited tospecific synthetic methods, specific components, or to particularcompositions. It is also to be understood that the terminology usedherein is for the purpose of describing particular embodiments only andis not intended to be limiting.

As used in the specification and the appended claims, the singular forms“a,” “an” and “the” include plural referents unless the context clearlydictates otherwise. Ranges may be expressed herein as from “about” oneparticular value, and/or to “about” another particular value. When sucha range is expressed, another embodiment includes¬ from the oneparticular value and/or to the other particular value. Similarly, whenvalues are expressed as approximations, by use of the antecedent“about,” it will be understood that the particular value forms anotherembodiment. It will be further understood that the endpoints of each ofthe ranges are significant both in relation to the other endpoint, andindependently of the other endpoint.

“Optional” or “optionally” means that the subsequently described eventor circumstance may or may not occur, and that the description includesinstances where said event or circumstance occurs and instances where itdoes not.

Throughout the description and claims of this specification, the word“comprise” and variations of the word, such as “comprising” and“comprises,” means “including but not limited to,” and is not intendedto exclude, for example, other additives, components, integers or steps.“Exemplary” means “an example of” and is not intended to convey anindication of a preferred or ideal embodiment. “Such as” is not used ina restrictive sense, but for explanatory purposes.

Disclosed are components that can be used to perform the disclosedmethods and systems. These and other components are disclosed herein,and it is understood that when combinations, subsets, interactions,groups, etc. of these components are disclosed that while specificreference of each various individual and collective combinations andpermutation of these may not be explicitly disclosed, each isspecifically contemplated and described herein, for all methods andsystems. This applies to all aspects of this application including, butnot limited to, steps in disclosed methods. Thus, if there are a varietyof additional steps that can be performed it is understood that each ofthese additional steps can be performed with any specific embodiment orcombination of embodiments of the disclosed methods.

The term “alkyl” as used herein is a branched or unbranched hydrocarbongroup such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,t-butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, dodecyl, and thelike. The alkyl group can also be substituted or unsubstituted. Unlessstated otherwise, the term “alkyl” contemplates both substituted andunsubstituted alkyl groups. The alkyl group can be substituted with oneor more groups including, but not limited to, alkoxy, alkenyl, alkynyl,cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aldehyde, amino,carboxylic acid, ester, ether, halide, hydroxy, ketone, nitro, silyl,sulfo-oxo, or thiol. An alkyl group which contains no double or triplecarbon-carbon bonds is designated a saturated alkyl group, whereas analkyl group having one or more such bonds is designated an unsaturatedalkyl group. Unsaturated alkyl groups having a double bond can bedesignated alkenyl groups, and unsaturated alkyl groups having a triplebond can be designated alkynyl groups. Unless specified to the contrary,the term alkyl embraces both saturated and unsaturated groups.

The term “cycloalkyl” as used herein is a non-aromatic carbon-based ringcomposed of at least three carbon atoms. Examples of cycloalkyl groupsinclude, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, etc. The term “heterocycloalkyl” is a cycloalkyl group asdefined above where at least one of the carbon atoms of the ring isreplaced with a heteroatom such as, but not limited to, nitrogen,oxygen, sulfur, selenium or phosphorus. The cycloalkyl group andheterocycloalkyl group can be substituted or unsubstituted. Unlessstated otherwise, the terms “cycloalkyl” and “heterocycloalkyl”contemplate both substituted and unsubstituted cyloalkyl andheterocycloalkyl groups. The cycloalkyl group and heterocycloalkyl groupcan be substituted with one or more groups including, but not limitedto, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl,heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide,hydroxy, ketone, nitro, silyl, sulfo-oxo, or thiol. A cycloalkyl groupwhich contains no double or triple carbon-carbon bonds is designated asaturated cycloalkyl group, whereas an cycloalkyl group having one ormore such bonds (yet is still not aromatic) is designated an unsaturatedcycloalkyl group. Unless specified to the contrary, the term cycloalkylembraces both saturated and unsaturated, non-aromatic, ring systems.

The term “aryl” as used herein is an aromatic ring composed of carbonatoms. Examples of aryl groups include, but are not limited to, phenyland naphthyl, etc. The term “heteroaryl” is an aryl group as definedabove where at least one of the carbon atoms of the ring is replacedwith a heteroatom such as, but not limited to, nitrogen, oxygen, sulfur,selenium or phosphorus. The aryl group and heteroaryl group can besubstituted or unsubstituted. Unless stated otherwise, the terms “aryl”and “heteroaryl” contemplate both substituted and unsubstituted aryl andheteroaryl groups. The aryl group and heteroaryl group can besubstituted with one or more groups including, but not limited to,alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl,heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide,hydroxy, ketone, nitro, silyl, sulfo-oxo, or thiol.

Exemplary heteroaryl and heterocyclyl rings include: benzimidazolyl,benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl,benzoxazolinyl, benzthiazolyl, benztriazolyl, benztetrazolyl,benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, 4aHcarbazolyl, carbolinyl, chromanyl, chromenyL cirrnolinyl,decahydroquinolinyl, 2H,6H˜1,5,2-dithiazinyl, dihydrofuro[2,3b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl, imidazolinyl,imidazolyl, 1H-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl,3H-indolyl, isatinoyl, isobenzofuranyl, isochromanyl, isoindazolyl,isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl,methylenedioxyphenyl, morpholinyl, naphthyridinyl,octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl,1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl,oxazolyl, oxindolyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl,phenazinyl, phenothiazinyl, phenoxathinyl, phenoxazinyl, phthalazinyl,piperazinyl, piperidinyl, piperidonyl, 4-piperidonyl, piperonyl,pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl,pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole,pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl,pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl,quinuclidinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl,tetrahydroquinolinyl, tetrazolyl, 6H-1,2,5-thiadiazinyl,1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl,1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl,thienooxazolyl, thienoimidazolyl, thiophenyl, and xanthenyl.

The terms “alkoxy,” “cycloalkoxy,” “heterocycloalkoxy,” “cycloalkoxy,”“aryloxy,” and “heteroaryloxy” have the aforementioned meanings foralkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, furtherproviding said group is connected via an oxygen atom.

As used herein, the term “substituted” is contemplated to include allpermissible substituents of organic compounds. In a broad aspect, thepermissible substituents include acyclic and cyclic, branched andunbranched, carbocyclic and heterocyclic, and aromatic and nonaromaticsubstituents of organic compounds. Illustrative substituents include,for example, those described below. The permissible substituents can beone or more and the same or different for appropriate organic compounds.For purposes of this disclosure, the heteroatoms, such as nitrogen, canhave hydrogen substituents and/or any permissible substituents oforganic compounds described herein which satisfy the valencies of theheteroatoms. This disclosure is not intended to be limited in any mannerby the permissible substituents of organic compounds. Also, the terms“substitution” or “substituted with” include the implicit proviso thatsuch substitution is in accordance with permitted valence of thesubstituted atom and the substituent, and that the substitution resultsin a stable compound, e.g., a compound that does not spontaneouslyundergo transformation such as by rearrangement, cyclization,elimination, etc. Unless specifically stated, a substituent that is saidto be “substituted” is meant that the substituent can be substitutedwith one or more of the following: alkyl, alkoxy, alkenyl, alkynyl,cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aldehyde, amino,carboxylic acid, ester, ether, halide, hydroxy, ketone, nitro, silyl,sulfo-oxo, or thiol. In a specific example, groups that are said to besubstituted are substituted with a protic group, which is a group thatcan be protonated or deprotonated, depending on the pH.

Unless specified otherwise, the term “patient” refers to any mammaliananimal, including but not limited to, humans.

Pharmaceutically acceptable salts are salts that retain the desiredbiological activity of the parent compound and do not impart undesirabletoxicological effects. Examples of such salts are acid addition saltsformed with inorganic acids, for example, hydrochloric, hydrobromic,sulfuric, phosphoric, and nitric acids and the like; salts formed withorganic acids such as acetic, oxalic, tartaric, succinic, maleic,fumaric, gluconic, citric, malic, methanesulfonic, p-toluenesulfonic,napthalenesulfonic, and polygalacturonic acids, and the like; saltsformed from elemental anions such as chloride, bromide, and iodide;salts formed from metal hydroxides, for example, sodium hydroxide,potassium hydroxide, calcium hydroxide, lithium hydroxide, and magnesiumhydroxide; salts formed from metal carbonates, for example, sodiumcarbonate, potassium carbonate, calcium carbonate, and magnesiumcarbonate; salts formed from metal bicarbonates, for example, sodiumbicarbonate and potassium bicarbonate; salts formed from metal sulfates,for example, sodium sulfate and potassium sulfate; and salts formed frommetal nitrates, for example, sodium nitrate and potassium nitrate.Pharmaceutically acceptable and non-pharmaceutically acceptable saltsmay be prepared using procedures well known in the art, for example, byreacting a sufficiently basic compound such as an amine with a suitableacid comprising a physiologically acceptable anion. Alkali metal (forexample, sodium, potassium, or lithium) or alkaline earth metal (forexample, calcium) salts of carboxylic acids can also be made.

Disclosed herein are compounds having the formula:

and pharmaceutically acceptable salts thereof,wherein Ar¹ and Ar² are independently aryl and heteroaryl groups;L¹ and L² are optionally present linking groups;R¹ is selected from R^(1a) or OR^(1a), wherein R^(1a) is selected fromhydrogen or C₁₋₈alkyl;R² is selected from R^(2a) or OR^(2a), wherein R^(2a) is selected fromhydrogen or C₁₋₈alkyl;Q¹ is absent, or a group having the formula —CR^(q1)R^(q1′)—; whereinR^(q1) is selected from R^(q1a), OR^(q1a), N(R^(q1a))₂, SO₂R^(q1a),SO₂N(R^(q1a))₂, C(O)R^(q1a); C(O)OR^(q1a), OC(O)R^(q1a);C(O)N(R^(q1a))₂, N(R^(q1a))C(O)R^(q1a), OC(O)N(R^(q1a))₂,N(R^(q1a))C(O)N(R^(q1a))₂, wherein R^(q1a) is in each case independentlyselected from hydrogen, C₁₋₈alkyl, C₂₋₈alkenyl, C₂₋₈alkynyl, aryl,C₁₋₈heteroaryl, C₃₋₈cycloalkyl, or C₁₋₈heterocyclyl;R^(q1) is selected from R^(q1a), OR^(q1a), N(R^(q1a))₂, SO₂R^(q1a),SO₂N(R^(q1a))₂, C(O)R^(q1a); C(O)OR^(q1a), OC(O)R^(q1′a);C(O)N(R^(q1a))₂, N(R^(q1′a))C(O)R^(q1′a), OC(O)N(R^(q1′a))₂,N(R^(q1′a))C(O)N(R^(q1′a))₂, wherein R^(q1a) is in each caseindependently selected from hydrogen, C₁₋₈alkyl, C₂₋₈alkenyl,C₂₋₈alkynyl, aryl, C₁₋₈heteroaryl, C₃₋₈cycloalkyl, or C₁₋₈heterocyclyl;Q² is absent, or a group having the formula —CR^(q2)R^(q2′)—; whereinR^(q2) is selected from R^(q2a), OR^(q2a), N(R^(q2a))₂, SO₂R^(q2a),SO₂N(R^(q2a))₂, C(O)R^(q2a); C(O)OR^(q2a), OC(O)R^(q2a);C(O)N(R^(q2a))₂, N(R^(q2a))C(O)R^(q2a), OC(O)N(R^(q2a))₂,N(R^(q2a))C(O)N(R^(q2a))₂, wherein R^(q2a) is in each case independentlyselected from hydrogen, C₁₋₈alkyl, C₂₋₈alkenyl, C₂₋₈alkynyl, aryl,C₁₋₈heteroaryl, C₃₋₈cycloalkyl, or C₁₋₈heterocyclyl;R^(q2′) is selected from R^(q2′a), OR^(q2′a), N(R^(q2′a))₂, SO₂R^(q2′a),SO₂N(R^(q2′a))₂, C(O)R^(q2′a); C(O)OR^(q2′a), OC(O)R^(q2′a);C(O)N(R^(q2′a))₂, N(R^(q2′a))C(O)R^(q2′a), OC(O)N(R^(q2′a))₂,N(R^(q2′a))C(O)N(R^(q2′a))₂, wherein R^(q2′a) is in each caseindependently selected from hydrogen, C₁₋₈alkyl, C₂₋₈alkenyl,C₂₋₈alkynyl, aryl, C₁₋₈heteroaryl, C₃₋₈cycloalkyl, or C₁₋₈heterocyclyl;

Z is O, S, or NR³;

R³ is selected from R^(3a), OR^(3a), N(R^(3a))₂, SO₂R^(3a),SO₂N(R^(3a))₂, C(O)R^(3a); C(O)OR^(3a), OC(O)R^(3a); C(O)N(R^(3a))₂,N(R^(3a))C(O)R^(3a), OC(O)N(R^(3a))₂, N(R^(3a))C(O)N(R^(3a))₂, whereinR^(3a) is in each case independently selected from hydrogen, C₁₋₈alkyl,C₂₋₈alkenyl, C₂₋₈alkynyl, aryl, C₁₋₈heteroaryl, C₃₋₈cycloalkyl, orC₁₋₈heterocyclyl;wherein any two or more of R¹, R², R³, L¹, L², Ar¹, or Ar² may togetherform a ring.

Suitable aryl and heteroaryl groups include those having the formula:

wherein X¹ is O, Se, Se, NR^(x), or an olefin having the formula—C(R)═C(R)—; X² is CR or N;R^(x) is hydrogen, C₁₋₈alkyl, C₂₋₈alkenyl, C₂₋₈alkynyl, aryl,heteroaryl, C₃₋₈cycloalkyl, or C₁₋₈heteroaryl;R is in each case independently selected from R^(a), OR^(a), N(R^(a))₂,SR^(a), SO₂R^(a), SO₂N(R^(a))₂, C(O)R^(a); C(O)OR^(a), OC(O)R^(a);C(O)N(R^(a))₂, N(R^(a))C(O)R^(a), OC(O)N(R^(a))₂, N(R^(a))C(O)N(R^(a))₂,wherein R^(a) is in each case independently selected from hydrogen,C₁₋₈alkyl, C₂₋₈alkenyl, C₂₋₈alkynyl, aryl, C₁₋₈heteroaryl,C₃₋₈cycloalkyl, or C₁₋₈heterocyclyl; wherein any two or more of R,R^(a), R^(x), L¹ or R¹ may together form a ring.

Exemplary aryl and heteroaryl groups include monocyclic systems likephenyl, pyridinyl, pyrrolyl, pyrimidinyl, pyrazinyl, furanyl,imidazolyl, triazinyl, oxazolyl, thiazolyl, azepinyl, and diazepinyl;bicyclic systems including benzo-fused variants of the above, includingnapthyl, quinolinyl, isoquinolinyl, benzofuran, indole, benzothiphene,and the like.

Other groups include purine and pteridine systems; polycyclic systems,e.g., ring systems having three or more fused rings can also be presentin the compounds of the invention. Aryl and heteroaryl groups can alsobe substituted one or more times with groups as defined herein.

In some embodiments, Ar¹ can be a monocyclic group having the structure:

wherein R is in each case independently selected from R^(a), OR^(a),N(R^(a))₂, SR^(a), SO₂R^(a), SO₂N(R^(a))₂, C(O)R^(a); C(O)OR^(a),OC(O)R^(a); C(O)N(R^(a))₂, N(R^(a))C(O)R^(a), OC(O)N(R^(a))₂,N(R^(a))C(O)N(R^(a))₂, wherein R^(a) is in each case independentlyselected from hydrogen, C₁₋₈alkyl, C₂₋₈alkenyl, C₂₋₈alkynyl, aryl,C₁₋₈heteroaryl, C₃₋₈cycloalkyl, or C₁₋₈heterocyclyl;wherein any two or more of R, R^(a), R^(x), L¹ or R¹ may together form aring.

In certain embodiments, Ar¹ has the structure:

wherein X¹ is O, Se, Se, NR^(x), or an olefin having the formula—C(R)═C(R)—, X² is CR, or N;R^(x) is hydrogen, C₁₋₈alkyl, C₂₋₈alkenyl, C₂₋₈alkynyl, aryl,heteroaryl, C₃₋₈cycloalkyl, and C₁₋₈heteroaryl;R^(z) is in each case independently selected from R^(za), OR^(za),N(R^(za))₂, SR^(za), SO₂R^(za), SO₂N(R^(za))₂, C(O)R^(za); C(O)OR^(za),OC(O)R^(za); C(O)N(R^(za))₂, N(R^(za))C(O)R^(za), OC(O)N(R^(za))₂,N(R^(za))C(O)N(R^(za))₂, wherein R^(za) is in each case independentlyselected from hydrogen, C₁₋₈alkyl, C₂₋₈alkenyl, C₂₋₈alkynyl, aryl,C₁₋₈heteroaryl, C₃₋₈cycloalkyl, or C₁₋₈heterocyclyl;wherein any two or more of R, R^(za), R^(x), L¹ or R¹ may together forma ring.

In certain preferred embodiments, Ar¹ is a phenyl group having thestructure:

-   -   wherein,    -   R⁵ is selected from R^(5a), OR^(5a), N(R^(5a))₂, SiR^(5a) ₃,        SR^(5a), SO₂R^(5a), SO₂N(R^(5a))₂, C(O)R^(5a); C(O)OR^(5a),        OC(O)R^(5a); C(O)N(R^(5a))₂, N(R^(5a))C(O)R^(5a),        OC(O)N(R^(5a))₂, N(R^(5a))C(O)N(R^(5a))₂, F, Cl, Br, I, cyano,        and nitro, wherein R^(5a) is in each case independently selected        from hydrogen, C₁₋₈alkyl, C₂₋₈alkenyl, C₂₋₈alkynyl, aryl,        C₁₋₈heteroaryl, C₃₋₈cycloalkyl, or C₁₋₈heterocyclyl;    -   R⁶ is selected from R^(6a), OR^(6a), N(R^(6a))₂, SiR^(6a) ₃,        SR^(6a), SO₂R^(6a), SO₂N(R^(6a))₂, C(O)R^(6a); C(O)OR^(6a),        OC(O)R^(6a); C(O)N(R^(6a))₂, N(R^(6a))C(O)R^(6a),        OC(O)N(R^(6a))₂, N(R^(6a))C(O)N(R^(6a))₂, F, Cl, Br, I, cyano,        and nitro, wherein R^(6a) is in each case independently selected        from hydrogen, C₁₋₈alkyl, C₂₋₈alkenyl, C₂₋₈alkynyl, aryl,        C₁₋₈heteroaryl, C₃₋₈cycloalkyl, or C₁₋₈heterocyclyl;    -   R⁷ is selected from R^(7a), OR^(7a), N(R^(7a))₂, SiR^(7a) ₃,        SR^(7a), SO₂R^(7a), SO₂N(R^(7a))₂, C(O)R^(7a); C(O)OR^(7a),        OC(O)R^(7a); C(O)N(R^(7a))₂, N(R^(7a))C(O)R^(7a),        OC(O)N(R^(7a))₂, N(R^(7a))C(O)N(R^(7a))₂, F, Cl, Br, I, cyano,        and nitro, wherein R^(7a) is in each case independently selected        from hydrogen, C₁₋₈alkyl, C₂₋₈alkenyl, C₂₋₈alkynyl, aryl,        C₁₋₈heteroaryl, C₃₋₈cycloalkyl, or C₁₋₈heterocyclyl;    -   R⁸ is selected from R^(8a), OR^(8a), N(R^(8a))₂, SiR^(8a) ₃,        SR^(8a), SO₂R^(8a), SO₂N(R^(8a))₂, C(O)R^(8a); C(O)OR^(8a),        OC(O)R^(8a); C(O)N(R^(8a))₂, N(R^(8a))C(O)R^(8a),        OC(O)N(R^(8a))₂, N(R^(8a))C(O)N(R^(8a))₂, F, Cl, Br, I, cyano,        and nitro, wherein R^(8a) is in each case independently selected        from hydrogen, C₁₋₈alkyl, C₂₋₈alkenyl, C₂₋₈alkynyl, aryl,        C₁₋₈heteroaryl, C₃₋₈cycloalkyl, or C₁₋₈heterocyclyl;    -   R⁹ is selected from R^(9a), OR^(9a), N(R^(9a))₂, SiR^(9a) ₃,        SR^(9a), SO₂R^(9a), SO₂N(R^(9a))₂, C(O)R^(9a); C(O)OR^(9a),        OC(O)R^(9a); C(O)N(R^(9a))₂, N(R^(9a))C(O)R^(9a),        OC(O)N(R^(9a))₂, N(R^(9a))C(O)N(R^(9a))₂, F, Cl, Br, I, cyano,        and nitro, wherein R^(9a) is in each case independently selected        from hydrogen, C₁₋₈alkyl, C₂₋₈alkenyl, C₂₋₈alkynyl, aryl,        C₁₋₈heteroaryl, C₃₋₈cycloalkyl, or C₁₋₈heterocyclyl;        wherein any two or more of L¹, R¹, R⁵, R⁶, R⁷, R⁸, and R⁹ may        together form a ring.

Various substitution patterns can be present in Ar¹. Ar¹ can be amonosubstituted aryl or heteroaryl ring. For instance, in someembodiments each of R⁶, R⁷, R⁸, and R⁹ are hydrogen, and R⁵ is asdefined above; each of R⁵, R⁷, R⁸, and R⁹ are hydrogen, and R⁶ is asdefined above; each of R⁵, R⁶, R⁸, and R⁹ are hydrogen, and R⁷ is asdefined above; each of R⁵, R⁶, R⁷, and R⁹ are hydrogen, and R⁸ is asdefined above; or each of R⁵, R⁶, R⁷, and R⁸ are hydrogen, and R⁹ is asdefined above. In other embodiments, Ar¹ can be a disubstituted aryl orheteroaryl ring. For instance, in some embodiments each of R⁷, R⁸, andR⁹ are hydrogen, and R⁵ and R⁶ are as defined above; each of R⁶, R⁸, andR⁹ are hydrogen, and R⁵ and R⁷ are as defined above; each of R⁶, R⁷, andR⁹ are hydrogen, and R⁵ and R⁸ are as defined above; each of R⁶, R⁷, andR⁸ are hydrogen, and R⁵ and R⁹ are as defined above; each of R⁵, R⁸, andR⁹ are hydrogen, and R⁶ and R⁷ are as defined above; each of R⁵, R⁷, andR⁹ are hydrogen, and R⁶ and R⁸ are as defined above; or each of R⁵, R⁷,and R⁸ are hydrogen, and R⁶ and R⁹ are as defined above.

Particularly preferred R⁵, R⁶, R⁷, R⁸, and R⁹ groups include C₁₋₄alkyl(e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, andisobutyl), C₁₋₄alkoxy (e.g., methoxy, ethoxy, n-propoxy, isopropoxy,n-butoxy, sec-butoxy, and isobutoxy), C₁₋₄haloalkyl (including, but notlimited to trifluromethyl, 2,2,2-trifluoroethyl, and the like),C₁₋₄haloalkoxy (including, but not limited to trifluromethoxy,2,2,2-trifluoroethoxy, and the like), F, Cl, Br, or I.

In certain embodiments, two of R⁵, R⁶, R⁷, R⁸, and R⁹ are alkoxy, andtogether form a ring. For instance, R⁶ and R⁷ can each be alkoxy and cantogether form a ring:

wherein A is an optionally substituted C₁₋₄alkyl group, for instance CH₂or CH₂CH₂. In other embodiments, R⁵ and R⁶ are each alkoxy and cantogether form a ring.

In certain embodiments, Ar¹ can be group having the formula:

wherein R⁵, R⁶, R⁷, R⁸, and R⁹ have the aforementioned meanings. Incertain embodiments R⁵, R⁶, R⁷, R⁸, and R⁹ can be independently selectedfrom C₁₋₄alkyl, C₁₋₄alkoxy, C₁₋₄haloalkyl, C₁₋₄haloalkoxy, F, Cl, Br, orI.

In other embodiments, one or more of R⁵, R⁶, R⁷, R⁸, and R⁹ is apoly(ethylene glycol) moiety having the formula R—(OCH₂CH₂)_(n)—O—,wherein R is hydrogen or C₁₋₄alkyl, and n is 1, 2, 3, 4, 5, 6, 7, 8, 9,10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20. In other embodiments, nis a number greater than 20. In some instances, R⁵, R⁸ and R⁹ are eachhydrogen, and R⁶ and R⁷ are a poly(ethylene glycol) moiety as definedabove.

L¹, when present, can be an optionally substituted C₁₋₈alkyl group; anoptionally substituted C₂₋₈alkenyl group; an optionally substitutedC₂₋₈alkynyl group; an optionally substituted aryl group; an optionallysubstituted C₁₋₈heteroaryl group; an optionally substitutedC₃₋₈cycloalky group; or an optionally substituted C₁₋₈heterocyclylgroup. Substituents on the L¹ group can form a ring with any of R¹, R²,R³, L², Ar¹, or Ar².

In some instance, L¹ includes a ring system, which can be aryl,heteroaryl, cycloalkyl, and heterocyclyl. For instance, L¹ can be anaromatic system having the formula:

wherein p can be 0, 1, 2, 3, 4, 5, or 6;o can be 0, 1, 2, 3, 4, 5, or 6; andCy is an optionally substituted aryl group; an optionally substitutedC₁₋₈heteroaryl group; an optionally substituted C₃₋₈cycloalkyl group; oran optionally substituted C₁₋₈heterocyclyl group. Exemplary Cy systemsinclude cyclopropane, cyclobutane, cyclopentane, cyclohexane,cycloheptane, cyclooctane, and various bicyclo and tricyclo derivativesthereof, oxirane, oxetane, dihydrofuran, tetrahydrofuran, pyrrolidine,imidazolidine, oxazolidine, thiazolidine, dioxolane, dithiolane,tetrazole, oxazole, imidazole, thiazole, piperidine, tetrahydropyran,piperazine, pyridine, morpholine, dioxane, azepane, oxepane, azepine,oxepine, and others. The —(CH₂)_(P)— and —(CH₂)_(o)— groups may bebonded to a ring carbon or nitrogen.

In some embodiments, L¹ is a group having the formula —(CR⁴R^(4′))_(n)—,wherein:

n is 0, 1, 2, 3, 4, 5, 6, 7, or 8;R⁴ is in each case independently selected from R^(4a), OR^(4a),N(R^(4a))₂, SiR^(4a) ₃, SR^(4a), SO₂R^(4a), SO₂N(R^(4a))₂, C(O)R^(4a);C(O)OR^(4a), OC(O)R^(4a); C(O)N(R^(4a))₂, N(R^(4a))C(O)R^(4a),OC(O)N(R^(4a))₂, N(R^(4a))C(O)N(R^(4a))₂, F, Cl, Br, I, cyano, andnitro, wherein R^(4a) is in each case independently selected fromhydrogen, C₁₋₈alkyl, C₂₋₈alkenyl, C₂₋₈alkynyl, aryl, C₁₋₈heteroaryl,C₃₋₈cycloalkyl, or C₁₋₈heterocyclyl;R^(4′) is in each case independently selected from R^(4′a), OR^(4′a),N(R^(4′a))₂, SiR^(4′a) ₃, SR^(4′a), SO₂R^(4′a), SO₂N(R^(4′a))₂,C(O)R^(4′a); C(O)OR^(4′a), OC(O)R^(4′a); C(O)N(R^(4′a))₂,N(R^(4′a))C(O)R^(4′a), OC(O)N(R^(4′a))₂, N(R^(4′a))C(O)N(R^(4′a))₂, F,Cl, Br, I, cyano, and nitro, wherein R^(4′a) is in each caseindependently selected from hydrogen, C₁₋₈alkyl, C₂₋₈alkenyl,C₂₋₈alkynyl, aryl, C₁₋₈heteroaryl, C₃₋₈cycloalkyl, or C₁₋₈heterocyclyl;wherein any two of R⁴ and R^(4′) may together form a carbonyl, imine,double bond, or triple bond; and wherein any two or more of R¹, R³, R⁴,R^(4′), R⁵, R⁶, R⁷, R⁸, and R⁹ may together form a ring. In certainembodiments, R⁴ and R^(4′) are in each case hydrogen. In furtherembodiments, R⁴ and R^(4′) are in each case hydrogen, and n is 1, 2, or3. In other embodiments, L¹ is absent, e.g., n is 0.

L², when present, can be an optionally substituted C₁₋₈alkyl group; anoptionally substituted C₂₋₈alkenyl group; an optionally substitutedC₂₋₈alkynyl group; an optionally substituted aryl group; an optionallysubstituted C₁₋₈heteroaryl group; an optionally substitutedC₃₋₈cycloalky group; or an optionally substituted C₁₋₈heterocyclylgroup. Substituents on the L² group can form a ring with any of R¹, R²,R³, L¹, Ar¹, or Ar².

In some instance, L² includes a ring system, which can be aryl,heteroaryl, cycloalkyl, and heterocyclyl. For instance, L² can be anaromatic system having the formula:

wherein p can be 0, 1, 2, 3, 4, 5, or 6;o can be 0, 1, 2, 3, 4, 5, or 6; andCy is an optionally substituted aryl group; an optionally substitutedC₁₋₈heteroaryl group; an optionally substituted C₃₋₈cycloalkyl group; oran optionally substituted C₁₋₈heterocyclyl group. Exemplary Cy systemsinclude cyclopropane, cyclobutane, cyclopentane, cyclohexane,cycloheptane, cyclooctane, and various bicyclo and tricyclo derivativesthereof, oxirane, oxetane, dihydrofuran, tetrahydrofuran, pyrrolidine,imidazolidine, oxazolidine, thiazolidine, dioxolane, dithiolane,tetrazole, oxazole, imidazole, thiazole, piperidine, tetrahydropyran,piperazine, pyridine, morpholine, dioxane, azepane, oxepane, azepine,oxepine, and others. The —(CH₂)_(P)— and —(CH₂)_(o)— groups may bebonded to a ring carbon or nitrogen.

In some embodiments, L² is a group having the formula—(CR¹⁰R^(10′))_(n′)—, wherein:

n′ is from 0-8;

R¹⁰ is in each case independently selected from R^(10a), OR^(10a),N(R^(10a))₂, SiR^(10a) ₃, SR^(10a), SO₂R^(10a), SO₂N(R^(10a))₂,C(O)R^(10a); C(O)OR^(10a), OC(O)R^(10a); C(O)N(R^(10a))₂,N(R^(10a))C(O)R^(10a), OC(O)N(R^(10a))₂, N(R^(10a))C(O)N(R^(10a))₂, F,Cl, Br, I, cyano, and nitro, wherein R^(10a) is in each caseindependently selected from hydrogen, C₁₋₈alkyl, C₂₋₈alkenyl,C₂₋₈alkynyl, aryl, C₁₋₈heteroaryl, C₃₋₈cycloalkyl, or C₁₋₈heterocyclyl;

R^(10′) is in each case independently selected from R^(10′a), OR^(10′a),N(R^(10′a))₂, SiR^(10′a) ₃, SR^(10′a), SO₂R^(10′a), SO₂N(R^(10′a))₂,C(O)R^(10′a); C(O)OR^(10′a), OC(O)R^(10′a); C(O)N(R^(10′a))₂,N(R^(10′a))C(O)R^(10′a), OC(O)N(R^(10′a))₂, N(R^(10′a))C(O)N(R^(10′a))₂,F, Cl, Br, I, cyano, and nitro, wherein R^(10′a) is in each caseindependently selected from hydrogen, C₁₋₈alkyl, C₂₋₈alkenyl,C₂₋₈alkynyl, aryl, C₁₋₈heteroaryl, C₃₋₈cycloalkyl, or C₁₋₈heterocyclyl;

wherein any two of R¹⁰ and R^(10′) may together form a carbonyl, imine,double bond or triple bond; and wherein any two or more of R¹, R³, Ar²,R¹⁰, and R¹⁰ may together form a ring.

In certain embodiments, L² is absent, e.g., n′ is 0.

Exemplary Ar² groups include aryl and heteroaryl moeities, optionallysubstituted with one or more further aryl or heteroaryl groups. In someinstances, Ar² has the formula:

-   -   wherein    -   R¹⁰ is selected from R^(10a), OR^(10a), N(R^(10a))₂, SiR^(10a)        ₃, SR^(10a), SO₂R^(10a), SO₂N(R^(10a))₂, C(O)R^(10a);        C(O)OR^(10a), OC(O)R^(10a); C(O)N(R^(10a))₂,        N(R^(10a))C(O)R^(10a), OC(O)N(R^(10a))₂,        N(R^(10a))C(O)N(R^(10a))₂, F, Cl, Br, I, cyano, and nitro,        wherein R^(10a) is in each case independently selected from        hydrogen, C_(1-13a)lkyl, C_(2-13a)lkenyl, C_(2-13a)lkynyl, aryl,        C₁₋₈heteroaryl, C₃₋₈cycloalkyl, or C₁₋₈heterocyclyl;    -   R¹¹ is selected from R^(11a), OR^(11a), N(R^(11a))₂, SiR^(11a)        ₃, SR^(11a), SO₂R^(11a), SO₂N(R^(11a))₂, C(O)R^(11a);        C(O)OR^(11a), OC(O)R^(11a); C(O)N(R^(11a))₂,        N(R^(11a))C(O)R^(11a), OC(O)N(R^(11a))₂,        N(R^(11a))C(O)N(R^(11a))₂, F, Cl, Br, I, cyano, and nitro,        wherein R^(11a) is in each case independently selected from        hydrogen, C_(1-13a)lkyl, C_(2-13a)lkenyl, C_(2-13a)lkynyl, aryl,        C₁₋₈heteroaryl, C₃₋₈cycloalkyl, or C₁₋₈heterocyclyl;    -   R¹² is selected from R^(12a), OR^(12a), N(R^(12a))₂, SiR^(12a)        ₃, SR^(12a), SO₂R^(12a), SO₂N(R^(12a))₂, C(O)R^(12a);        C(O)OR^(12a), OC(O)R^(12a); C(O)N(R^(12a))₂,        N(R^(12a))C(O)R^(12a), OC(O)N(R^(12a))₂,        N(R^(12a))C(O)N(R^(12a))₂, F, Cl, Br, I, cyano, and nitro,        wherein R^(12a) is in each case independently selected from        hydrogen, C_(1-13a)lkyl, C_(2-13a)lkenyl, C_(2-13a)lkynyl, aryl,        C₁₋₈heteroaryl, C₃₋₈cycloalkyl, or C₁₋₈heterocyclyl;    -   R¹³ is selected from R^(13a), OR^(13a), N(R^(13a))₂, SiR^(13a)        ₃, SR^(13a), SO₂R^(13a), SO₂N(R^(13a))₂, C(O)R^(13a);        C(O)OR^(13a), OC(O)R^(13a); C(O)N(R^(13a))₂,        N(R^(13a))C(O)R^(13a), OC(O)N(R^(13a))₂,        N(R^(13a))C(O)N(R^(13a))₂, F, Cl, Br, I, cyano, and nitro,        wherein R^(13a) is in each case independently selected from        hydrogen, C_(1-13a)lkyl, C_(2-13a)lkenyl, C_(2-13a)lkynyl, aryl,        C₁₋₈heteroaryl, C₃₋₈cycloalkyl, or C₁₋₈heterocyclyl;    -   R¹⁴ is selected from R^(14a), OR^(14a), N(R^(14a))₂, SiR^(14a)        ₃, SR^(14a), SO₂R^(14a), SO₂N(R^(14a))₂, C(O)R^(14a);        C(O)OR^(14a), OC(O)R^(14a); C(O)N(R^(14a))₂,        N(R^(14a))C(O)R^(14a), OC(O)N(R^(14a))₂,        N(R^(14a))C(O)N(R^(14a))₂, F, Cl, Br, I, cyano, and nitro,        wherein R^(14a) is in each case independently selected from        hydrogen, C_(1-13a)lkyl, C_(2-13a)lkenyl, C_(2-13a)lkynyl, aryl,        C₁₋₈heteroaryl, C₃₋₈cycloalkyl, or C₁₋₈heterocyclyl;        wherein any two or more of L¹, R¹, R³, R¹⁰, R¹¹, R¹², R¹³, and        R¹⁴ may together form a ring.

Various substitution patterns can be present in Ar². Ar² can be amonosubstituted aryl or heteroaryl ring. For instance, in someembodiments each of R¹¹, R¹², R¹³, and R¹⁴ are hydrogen, and R¹⁰ is asdefined above; each of R¹⁰, R¹², R¹³, and R¹⁴ are hydrogen, and R¹¹ isas defined above; each of R¹⁰, R¹¹, R¹³, and R¹⁴ are hydrogen, and R¹²is as defined above; each of R¹⁰, R¹¹, R¹², and R¹⁴ are hydrogen, andR¹³ is as defined above; or each of R¹⁰, R¹¹, R¹², and R¹³ are hydrogen,and R¹⁴ is as defined above. In other embodiments, Ar¹ can be adisubstituted aryl or heteroaryl ring. For instance, in some embodimentseach of R¹², R¹³, and R¹⁴ are hydrogen, and R¹⁰ and R¹¹ are as definedabove; each of R¹¹, R¹³, and R¹⁴ are hydrogen, and R¹⁰ and R¹² are asdefined above; each of R¹¹, R¹², and R¹⁴ are hydrogen, and R¹⁰ and R¹³are as defined above; each of R¹¹, R¹², and R¹³ are hydrogen, and R¹⁰and R¹⁴ are as defined above; each of R¹⁰, R¹³, and R¹⁴ are hydrogen,and R¹¹ and R¹² are as defined above; each of R¹⁰, R¹², and R¹⁴ arehydrogen, and R¹¹ and R¹³ are as defined above; or each of R¹⁰, R¹², andR¹³ are hydrogen, and R¹¹ and R¹⁴ are as defined above.

Particular preferred R¹⁰, R¹¹, R¹², R¹³, and R¹⁴ groups include bicyclicaryl and heteroaryl groups having the formula:

wherein X¹ is O, Se, Se, NR^(x), or an olefin having the formula—C(R)═C(R)—, X² is CR, or N; R^(x) is hydrogen, C₁₋₈alkyl, C₂₋₈alkenyl,C₂₋₈alkynyl, aryl, heteroaryl, C₃₋₈cycloalkyl, and C₁₋₈heteroaryl;R^(y) is in each case independently selected from R^(ya), OR^(ya),N(R^(ya))₂, SR^(ya), SO₂R^(ya), SO₂N(R^(ya))₂, C(O)R^(ya); C(O)OR^(ya),OC(O)R^(ya); C(O)N(R^(ya))₂, N(R^(ya))C(O)R^(ya), OC(O)N(R^(ya))₂,N(R^(ya))C(O)N(R^(ya))₂, wherein R^(ya) is in each case independentlyselected from hydrogen, C₁₋₈alkyl, C₂₋₈alkenyl, C₂₋₈alkynyl, aryl,C₁₋₈heteroaryl, C₃₋₈cycloalkyl, or C₁₋₈heterocyclyl; wherein any two ormore of R, R^(ya), R^(x), R³, L² or R² may together form a ring.

In certain embodiments, Ar² can be a group having the formula:

wherein R¹⁰, R¹¹, R¹², R¹³, and R¹⁴have the aforementioned meanings. Incertain preferred embodiments, R¹¹ or R¹³ can be aryl or C₁₋₈heteroaryl.Exemplary R¹¹ and R¹³ groups include:

whereinX¹ is selected from an olefin having the formula —C(R^(x))═C(R^(x))—, ora heteroatom such as O, S, Se or NR⁴;X² is independently selected from CR^(x) or N;R⁴ is hydrogen, C₁₋₈alkyl, C₂₋₈alkenyl, C₂₋₈alkynyl, aryl, heteroaryl,C₃₋₈cycloalkyl, and C₁₋₈heteroaryl;R^(x) is in each case independently selected from R^(xa), OR^(xa),N(R^(xa))₂, SO₂R^(xa), SO₂N(R^(xa))₂, C(O)R^(xa); C(O)OR^(xa),OC(O)R^(xa); C(O)N(R^(xa))₂, N(R^(xa))C(O)R^(xa), OC(O)N(R^(xa))₂,N(R^(xa))C(O)N(R^(xa))₂, wherein R^(xa) is in each case independentlyselected from hydrogen, C₁₋₈alkyl, C₂₋₈alkenyl, C₂₋₈alkynyl, aryl,C₁₋₈heteroaryl, C₃₋₈cycloalkyl, or C₁₋₈heterocyclyl; and wherein any twoor more of R², L², R^(x), R³, R¹⁰, R¹², R¹³, and R¹⁴ may together form aring.

In some instances, any one or more of R¹⁰, R¹¹, R¹², R¹³, or R¹⁴ is anoptionally substituted ring system having the formula:

Although the above ring systems are depicted as unsubstituted, incertain embodiments additional substituents, as defined above, may bepresent.

In certain preferred embodiments, Q¹ and Q² are each absent, while inother embodiments, Q¹ is absent, and Q² is a group having the formula—(CR^(q2)R^(q2′))—, wherein R^(q2) is hydrogen and R^(q2′) is hydrogen,OH, or C₁₋₆alkyl. In some instances, Q² is absent, and Q¹ is a grouphaving the formula —(CR^(q1)R^(q1′))—, wherein R^(q1) is hydrogen andR^(q1′) is hydrogen, OH, or C₁₋₆alkyl.

A preferred group of compounds includes those in which both R¹ and R²are hydrogen, and other preferred compounds include those in which R¹and R² are each hydrogen, and Z is oxygen.

In other embodiments, Z is NR³, and R³ may form a ring with one or moreof L² or Ar². For instance, compounds having the formula:

wherein Ar¹, L², R¹⁰, R¹¹, R¹², and R¹³ are as defined above, and R³⁻¹⁴is a chemical bond, O, CH₂ or C(O).

In some embodiments are provided compounds having the formula:

wherein Ar¹, L¹, L², and Ar² have the aforementioned meanings. Incertain embodiments, L² is absent and L¹ is an optionally substitutedC₁₋₈alkyl group:

wherein Ar¹ and Ar² have the aforementioned meanings, n is an integerfrom 1-8, R^(L) is in each case independently selected from R^(La),OR^(La), N(R^(La))₂, SO₂R^(La), SO₂N(R^(La))₂, C(O)R^(La); C(O)OR^(La),OC(O)R^(La); C(O)N(R^(La))₂, N(R^(La))C(O)R^(La), OC(O)N(R^(La))₂,N(R^(La))C(O)N(R^(La))₂, wherein R^(La) is in each case independentlyselected from hydrogen, C₁₋₈alkyl, C₂₋₈alkenyl, C₂₋₈alkynyl, aryl,C₁₋₈heteroaryl, C₃₋₈cycloalkyl, or C₁₋₈heterocyclyl, wherein any two ormore of Ar¹, R^(L) and Ar² may together form a ring. In someembodiments, the compounds can have the formula:

In some cases, Ar² can be a monosubstituted aryl ring such as:

In certain embodiments, Ar² can be a disubstituted aryl ring

In certain embodiments, Z can be NR³, and R³ can form a ring with Ar².Exemplary embodiments include compounds having L² (as defined above) andcompounds in which L² is absent:

wherein Ar¹, L¹, L², n, R^(L), Ar² and R³ have the meanings given above.Also provided are compounds in which R³ and Ar² form a ring, and Ar² isan aryl ring:

wherein R³⁻¹⁴ is selected from a chemical bond, C₁₋₄alkyl, O, or C(O),and Ar¹, L¹, R^(L), n, R¹⁰, R¹¹, R¹², and R¹³ have the aforementionedmeanings.

In some embodiments, the disruptor compounds can have the formula:

wherein X is O or NH, and L², L¹, R¹⁰, R¹¹, R¹², R¹³, and R¹⁴ are asdefined above. In certain embodiments, R¹⁰, R¹¹, and R¹⁴ are eachhydrogen, and R¹² and R¹³ are each C₁₋₄alkoxy, and may optionallytogether form a ring. In some instance, L² can be absent, aryl,C₁₋₃alkylene, especially methylene (CH₂), and heterocyclyl. Preferred L¹groups include C₁₋₃alkylene, especially methylene (CH₂). In certainembodiments, the disruptor compounds can have the formula:

Preferred C₁₋₄alkoxy groups include methoxy, and preferred ring systemsinclude dioxin (six member ring) and dioxolyl (five membered ring)systems. In certain cases, the disruptor compound can be:

The disrupter compounds disclosed herein may be used to treatneurological damage, for instance damage to neurons, especially neuronsin the central nervous system. Neuronal damage can be caused by avariety of conditions and events, such as ischemic stroke, hemorrhagicstroke or brain injury, such as traumatic brain injury. The disruptercompounds disclosed herein may be used to treat a variety ofneurodegenerative diseases. Neurodegenerative diseases are typicallycharacterized by the progressive loss of structure or function ofneurons, such as neurons within the cerebral cortex, basal ganglia,cerebellum, brain stem or motor systems. Neurodegenerative disordersinclude, but are not limited to, Alzheimer's disease, Parkinson'sdisease, Huntington's disease, ALS, multiple sclerosis, Lewy bodydementia, vascular dementia, progressive supranuclear palsy,corticobasal degeneration, multiple system atrophy and frontotemporaldementia.

Methods of administering therapeutic compounds are well known in theart. In some embodiments of the disclosed methods, the disclosedcompounds are administered to a subject for the treatment of cerebralischemia (for instance caused by cardiac arrest), stroke (such asischemic stroke or hemorrhagic stroke), CNS trauma/injury, traumaticbrain injury, a neurodegenerative disease, or any other conditionassociated with neuronal damage and/or neuronal cell death. Whenadministering such compounds, one must consider the appropriate targetsite based on the disease to be treated. If the site of action is thecentral nervous system, the compound must be able to cross the bloodbrain barrier (BBB), injected intrathecally, or be delivered directly tothe target site in the brain.

In some embodiments, the disclosed compounds may be provided in the formof a pharmaceutical composition such as but not limited to, unit dosageforms including tablets, capsules (filled with powders, pellets, beads,mini-tablets, pills, micro-pellets, small tablet units, multiple unitpellet systems (MUPS), disintegrating tablets, dispersible tablets,granules, and microspheres, multiparticulates), sachets (filled withpowders, pellets, beads, mini-tablets, pills, micro-pellets, smalltablet units, MUPS, disintegrating tablets, dispersible tablets,granules, and microspheres, multiparticulates), powders forreconstitution and sprinkles, transdermal patches, however, other dosageforms such as controlled release formulations, lyophilized formulations,modified release formulations, delayed release formulations, extendedrelease formulations, pulsatile release formulations, dual releaseformulations and the like. Liquid and semisolid dosage forms (liquids,suspensions, solutions, dispersions, ointments, creams, emulsions,microemulsions, sprays, patches, spot-on), parenteral, topical,inhalation, buccal, nasal etc. may also be envisaged under the ambit ofthe invention.

Suitable excipients may be used for formulating the dosage formaccording to the present invention such as, but not limited to, surfacestabilizers or surfactants, viscosity modifying agents, polymersincluding extended release polymers, stabilizers, disintegrants or superdisintegrants, diluents, plasticizers, binders, glidants, lubricants,sweeteners, flavoring agents, anti-caking agents, opacifiers,anti-microbial agents, antifoaming agents, emulsifiers, bufferingagents, coloring agents, carriers, fillers, anti-adherents, solvents,taste-masking agents, preservatives, antioxidants, texture enhancers,channeling agents, coating agents or combinations thereof.

In some embodiments, the disrupter compounds are administered by directinfusion into the brain, such as by intracerebroventricular (ICV)injection/infusion, intrastriatal injection, intranigral injection,intracerebral injection, infusion into the putamen, intrathecal infusion(such as by using an implanted pump) or by subcutaneous injection.Intranasal administration of compounds also leads to delivery to theCNS. Thus, in some examples, the disrupter compound is administeredintranasally

The compounds disclosed herein may be prepared using conventional ureaforming chemistries. Unsymmetrical ureas may be prepared using a Curtiusrearrangement, Lossen rearrangement, carbonylation of an azide in thepresence of an amine, or sequential reaction of amines withbiselectrophiles such as carbonyl di-imidazole or S,S-dimethyldithiocarbonate.

Examples

The following examples are for the purpose of illustration of theinvention only and are not intended to limit the scope of the presentinvention in any manner whatsoever.

The compound3-[3-(1,3-benzothiazol-2-yl)phenyl]-1-[(3,4-dimethoxyphenyl)methyl]urea), designated herein as Cpd5, was evaluated in vitro forinnate toxicity and then for neuroprotective actions in rat primaryculture cortical neurons. No neurotoxicity was observed atconcentrations as high as 30 μM (FIG. 7). We next examined whether Cpd5would provide neuroprotection against overnight applications ofthreo-beta-Benzyloxyaspartate (TBOA; 60 μM), a relatively non-selectiveglutamate uptake inhibitor (Shimamoto et al., 1998) that inducesgradual, NMDA receptor-mediated excitotoxicity in our culturesaccompanied by a pronounced increase in K⁺ currents (Yeh et al., 2017).We found that pre-loading (1 hr) and co-incubation with 10 μM Cpd5significantly diminished TBOA toxicity, an effect nearly identical tothe actions of 1 μM TAT-C1aB treatment.

A hallmark of Kv2.1-facilitated neuronal cell death is the accompanyingdramatic increase in delayed rectifier K⁺ currents as the result ofsyntaxin-dependent de novo Kv2.1 channel plasma membrane insertion (Palet al., 2006). Plasmid-mediated overexpression of the C1a region or theuse of the TAT-C1aB peptide can prevent the Kv2.1-mediated current surge(McCord et al., 2014; Yeh et al, 2017). To determine whether Cpd5 canachieve similar inhibition of current enhancement, we carried out wholecell patch clamp recordings of rat primary cortical culture neuronsafter co-incubation with TBOA (50 μM for 2 hr followed by 2 hr restingperiod). In strong agreement with our neuroprotection assays, we foundthat Cpd5 (10 μM) pre-loading (1 hr) and co-treatment with TBOAeffectively suppressed the post-injury enhancement of delayed rectifierK⁺ currents in neurons to levels comparable to uninjured neurons (FIG.2C). Most importantly, we found no significant effects of Cpd5incubation alone on basal K⁺ current densities (FIG. 2C), stronglysuggesting that pre-existing membrane-bound channels and the normaltrafficking of the channel during the 5 hours total of Cpd5 incubationare unaffected by this compound. This is consistent with previousfindings in cells expressing the C1a region or treated with TAT-C1aB(McCord et al., 2014; Yeh et al., 2017).

Because NMDA receptors mediate the neurotoxicity elicited byglutamate-uptake inhibitors (Blitzblau et al., 1996), it was necessaryto ensure Cpd5 did not inhibit Ca²⁺ responses mediated by thesereceptors, a major component of acute excitotoxicity (Sattler &Tymianski, 2001). We thus performed Fura-2 ratiometric Ca²⁺ imaging inrat cortical culture neurons during NMDA (30 μM with 10 μM glycine)exposure, noting a lack of any effect of concurrently-administrated Cpd5(10 μM) on NMDA-evoked Ca²⁺ responses (FIG. 2D). This strongly indicatesthat the aforementioned neuroprotective actions of Cpd5 likely did notoccur as a result of direct interference with the upstream components ofthe excitotoxic cascade. Rather, these findings are evidence that Cpd5,like TAT-C1aB, provide neuroprotection against TBOA-inducedexcitotoxicity specifically by preventing the expression of enhancedKv2.1-mediated K⁺ currents.

To confirm the molecular mechanism of Cpd5, we first performed furtherDMS analysis, revealing that the predicted pose of Cpd5 bound tosyntaxin does indeed recapitulate the aromatic ring-stacking of C1aB KWwith syntaxin F34, as well as three hydrogen bonds coordinating thewater molecules (FIG. 3A). In a far Western assay (Yeh et al., 2017), webiochemically confirmed that Cpd5 (100 μM) significantly reduced thebinding between syntaxin and Kv2.1 peptides containing the C1aB regionpreviously reported (Red sequences, FIG. 3B; (Yeh et al., 2017)). Atpeak values, the presence of Cpd5 reduced Kv2.1 peptides binding tosyntaxin by up to 60% (FIG. 3C). Next, we performed aco-immunoprecipitation assay of syntaxin and munc-18 in transfectedHEK293 cells incubated in the presence or absence of Cpd5. We found thatCpd5 (100 μM) robustly disrupts the binding between munc-18 and syntaxin(FIG. 4B). Of note, at the neuroprotective concentration of 10 μM, Cpd5did not displace munc-18 from syntaxin (FIG. 4C). Together, theseresults strongly suggest that the observed neuroprotective actions ofCpd5 are due to its binding to syntaxin F34, thus effectively preventingthe interaction of Kv2.1 with the SNARE protein.

The loss of munc-18 function blocks neurotransmitter release, causingmunc-18^(−/−) animals suffer paralysis and rapid globalneurodegeneration after birth (Verhage et al., 2000; Weimer et al.,2003). Although we did not find Cpd5 to be neurotoxic in vitro despiteits overlapping binding site with that of munc-18, it remained necessaryto evaluate the possibility of Cpd5 inducing irregularities in neuronalexcitability and synaptic functions. First, we examined the effects ofCpd5 (10 μM) on the intrinsic electrical properties of layer 5 pyramidaltract neurons in acute slices of mouse cerebral cortex. We were unableto detect any changes in membrane potential (FIG. 5A), input resistance(FIG. 5B), action potential threshold, width, and firing rate (FIG.5C-G), or F1CN channel-mediated (I_(h)) sag currents (FIG. 5H, I) inneurons treated with Cpd5 when compared to vehicle. We then measuredexcitatory synaptic potentials evoked in cortical layer 2/3 projectionneurons by local electrical stimulation in acute slices. No significantdifferences were detected in the threshold, amplitude or duration ofsynaptic potentials evoked in these cells during the application of Cpd5(10 μM) (FIG. 6A-C). These results demonstrate that at the therapeuticconcentration of 10 μM, Cpd5 does not appear to have any measurableaction on intrinsic or synaptic properties, potentially ruling outoff-target effects of the compound.

All animal protocols described here and below were approved by theInstitutional Animal Care and Use Committee of the University ofPittsburgh School of Medicine. Cortical neurons were prepared fromembryonic day 16-17 rats of either sex. Pregnant donor rats (CharlesRiver Laboratories) were killed by gradual CO₂ inhalation, an AmericanVeterinary Medical Association approved protocol (Leary et al., 2013).Cortices were dissociated with trypsin, and plated at 670,000 cells perwell on poly-L-ornithine glass coverslips in six-well plates.Non-neuronal cell proliferation was inhibited with 1-2 μM cytosinearabinoside at 15 days in vitro (DIV). All cortical culture experimentsshown here were performed on 18-25 DIV cultures.

DL-threo-β-benzyloxaspartate (TBOA; Tocris Bioscience) excitotoxicityassays were performed on cortical culture coverslips transferred into24-well plates containing 10 mM HEPES, 0.01% bovine serum albumin(BSA)-supplemented MEM without phenol red (MHB). On each individualplate, coverslips were treated with vehicle control or 75 μM TBOA inwells that had been preincubated for 1 hr with either 10 μM of theindicated treatment or vehicle at 37° C., 5% CO₂ for 24 hr. Followingthis exposure, external medium was collected for LDH colorimetricmeasurements using a toxicity kit (Sigma-Aldrich), as previouslydescribed 12. Each experiment contained three replicates of fourconditions (with/without TBOA, with/without treatment). Relativetoxicity was quantified as the LDH ratio of TBOA-treated over vehiclecontrol values within each experiment. For visualization of the cellcultures, coverslips were imaged at 20× using a QCapture camera system.

Intracellular Ca²⁺ measurements were performed on the same corticalculture preparations as above, but with 20 DIV cells plated on MatTekglass-bottom 35 mm culture dishes. At this developmental stage, neuronsrobustly express both GluN2A and GluN2B subunits of the NMDA receptor.Neurons were incubated with the fluorescent Ca²⁺ indicator Fura-2 AMester (5 μM; Invitrogen) with 0.02% Pluronic F-127 (Invitrogen) for 1 hat 37° C. Culture dishes were then mounted on an inverted microscopestage (Olympus) and continuously perfused with a 10 mM HEPES-bufferednormal salt solution. Perfusion rate (5 ml/min) was controlled with agravity flow and a rapid-switching local perfusion system (WarnerInstruments). Firmly attached refractile cells were identified asregions of interest (ROIs; 4 coverslips, ˜40 cells/coverslip). A ratioof fluorescence emission (F) at 510 nm in response to excitations at 340and 380 nm was acquired at 1 Hz (Fambda DG-4 and 10-B SmartShutter,Sutter Instruments) via camera (ORCAER, Hamamatsu) and saved to acomputer using HCImage (Hamamatsu). Baseline Ca²⁺ signals were recordedfor 2 min before the first application of NMDA (30 μM plus 10 μMglycine) with or without 10 μM cpd5 (Cat #MolPort-009-741-732, Molport).The second exposure to NMDA is given 4 minutes later. Peak increases inintracellular calcium concentration were measured by calculating F/Fo(F, peak fluorescence; Fo, average signal across 2 min baseline period).The area under the response for the first 15 min of NMDA application wasalso calculated.

Peptide spot array and far-Western assay. Peptide spot arrays (15 mers)spanning the proximal C-terminus residues 451-540 of rat Kv2.1 wereconstructed using the Spots-synthesis method. Standard9-fluorenylmethoxy carbonyl (Fmoc) chemistry was used to synthesize thepeptides and spot them onto nitrocellulose membranes prederivatized witha polyethylene glycerol spacer (Intavis). Fmoc protected and activatedamino acids were spotted in quadruplicates on 20-30 arrays on 75 by 25mm membranes using an Intavis MultiPep robot. The nitrocellulosemembrane containing the immobilized peptides were rehydrated inTris-buffered 0.1% Tween 20 (TBST) for 10 min, and then blocked for 1 hat room temperature (RT) with gentle shaking in TBST containing 5% (w/v)nonfat dry milk and then incubated with enriched STX1A proteincontaining the indicated concentrations of cpd5 for 1 h at RT withgentle shaking. Next, the membrane was incubated in primary antibody forsyntaxin 1A (Millipore, catalog #AB5820-50UL, RRID:AB_2216165) for 2 hat RT with gentle shaking, followed by washing with TBST. Finally, themembrane was incubated in secondary antibody (goat anti-rabbit DyLight800, catalog #355571, Thermo Fisher Scientific) for 45 min, washed for 3times 5 min in TBST, and visualized by infrared fluorescence (Li-Cor).Similar procedures were followed for the alanine scan study with 9-mers.

Cortical culture electrophysiology. Whole-cell patch-clamp experimentswere performed on rat cortical culture neurons prepared as described inthe LDH toxicity experiments. The TBOA treatment was reduced in severityin this experiment to limit extensive cell injury that would preventadequate patch clamp recordings. Prior to recording, coverslips weretreated with 50 μM TBOA in MHB for 2 hr. The treatment was terminatedwith 3×MHB washes and transferring the coverslip to a separate wellcontaining MHB to rest for 2 hr prior to electrophysiology recordingsand to allow for the expression of enhanced currents. For cpd5-treatedgroups, cells were pre-incubated for 1 hr in 10 μM cpd5 prior to theaddition of TBOA. Cpd5 was also present during the TBOA and thepost-TBOA incubation phases.

Recordings were carried out using 1.5 mm diameter borosilicate glasselectrodes (Sutter Instruments) made from a horizontal pipette puller at5-7 MΩ. The internal solution contains (in mM): 100 K-gluconate, 10 KCl,1 MgCl₂, 1 CaCl₂, 10 HEPES, 11 EGTA, 2.2 ATP, 0.33 GTP. The internalsolution was further adjusted to pH 7.2 and to 280 mOsm with theaddition of sucrose. The pH adjusted (7.2) external solution wascomposed of the following (in mM): 115 NaCl, 2.5 KCl, 2.0 MgCl2, 10HEPES, 10 D-glucose, and 0.25 μM TTX. Once whole-cell configuration hasbeen achieved, delayed rectifier currents were evoked with 185 msvoltage steps from a holding potential of −80 mV to +80 mV in +10 mVincrements. Recordings were filtered at 2 kHz and digitized at 10 kHz(Digidata 1440A, Molecular Devices). Series resistance was compensatedat 80% for all recordings. Analysis of current density was carried outat the +30 mV voltage step, taking the mean value of the steadystatecurrent between 150 and 175 ms over the cell capacitance. Normality ofthe data was confirmed via Shapiro-Wilk test.

Stereotaxic injections for electrophysiology. Male or female ICR miceP21-30 (Jackson Laboratory) were anesthetized with 3% isoflurane (1.5%maintenance) and placed on the stereotaxic frame (Kopf). Core bodytemperature was maintained at ˜37° C. with a heating pad and eyes wereprotected with ophthalmic ointment. Lidocaine (1%) was injected underthe scalp and an incision was made into the skin at the midline toexpose the skull. To retrogradely label corticocallosal neurons andcorticocollicular neurons in the auditory cortex, the contralateralauditory cortex (PLV −4, +4, +1 mm bregma) and the ipsilateral inferiorcolliculus (PLV −1, +1, −0.75 mm lambda) respectively were injected withretrograde tracer beads (Lumafluor) through a small craniotomy. A volumeof ˜0.12 μl fluorospheres was pressure injected (25 psi, 10 ms duration)from capillary pipettes (Drummond Scientific) with a Picospritzer(Parker-Hannifin). After injection, the pipette was held in the brainfor 2 min before slowly withdrawing. The scalp of the mouse was closedwith cyanoacrylate adhesive. Mice were injected with the non-steroidalanti-inflammatory drug carprofen at 5 mg/kg (Henry Schein Animal Health)for 24 hours prior to and 48 hours after surgery. Mice were monitoredfor signs of postoperative stress and pain.

Slice electrophysiology. Slice electrophysiology experiments wereperformed in mice at least 2 days after fluorospheres injections.Following anesthesia with isoflurane, mice were immediately decapitated.Brains were rapidly removed and coronal slices (300 μm) containing theauditory cortex were prepared in a cutting solution at 1° C. using aVibratome (VT1200 S; Leica). For evoked EPSC recordings, the cuttingsolution, pH 7.4, ˜300 mOsm, contained the following (in mM): 2.5 KCl,1.25 NaH₂PO₄, 25 NaHCO₃, 0.5 CaCl₂, 7 MgCl₂, 7 Glucose, 205 sucrose, 1.3ascorbic acid, and 3 sodium pyruvate (bubbled with 95% O₂/5% CO₂). Forevaluation of corticocollicular neuron electrical properties, thecutting solution, pH ˜7.4, contained the following (in mM): 135 NMDG, 1KCl, 1.2 KH₂PO₄, 1.5 MgCl₂, 1.5 CaCl2, 20 NaHCO₃, 10 D-Glucose. Theslices were then transferred and incubated at 34° C. for 30 min (bubbledwith 95% O₂/5% CO₂) prior to recording. The incubating and recordingsolution contained the following (in mM): 125 NaCl, 2.5 KCl, 1.25NaH₂PO₄, 25 NaHCO₃, 2 CaCl₂, 1 MgCl₂, 10 D-Glucose, 1.3 ascorbic acid,and 3 sodium pyruvate (bubbled with 95% O₂/5% CO₂). Slices were storedat room temperature until the time of recording. The flow rate of theACSF was ˜1.5 ml/min, and its temperature was maintained at 34° C. usingan in-line heating system (Warner). Both slice electrophysiologyexperiments were carried out using MultiClamp-700B amplifier equippedwith Digidata-1440A A/D converter and Clampex (Molecular Devices). Datawere sampled at 10 kHz and Bessel filtered at 4 kHz. Pipette capacitancewas compensated and series resistance for recordings was lower than 15MΩ and measured throughout the experiments. Recordings were excludedfrom further analysis if the series resistance changed by more than 15%compared to the baseline period.

To evoke AMPAR EPSCs, auditory cortex layer 2/3 neurons were stimulatedlocally with an Isoflex stimulator (AMPI), through a glass thetaelectrode containing ACSF, by a single 0.15 ms duration electrical pulseevery 30 sec. AMPAR EPSCs were recorded in voltage clamp mode at −70 mV(peak values were averaged over a 0.3 ms time window).

All data for intrinsic properties were acquired and analyzed within theEphus software package. Series resistance was determined involtage-clamp mode (command potential set at −70 mV) by giving a −5 mVvoltage step. Series resistance was determined by dividing the −5 mVvoltage step by the peak current value generated immediately after thestep in the command potential R_(input) was calculated in voltage-clampmode (command potential set to −70 mV) by giving a −5 mV step, whichresulted in transient current responses. The difference between baselineand steady-state hyperpolarized current (ΔI) was used to calculateR_(input) using the following formula: R_(input)=−5 mV/ΔI−R_(series).The average resting membrane potential (V_(m)) was calculated by holdingthe neuron in voltage-follower mode (current clamp, at I=0) ˜2 minutesafter breaking in and averaging the membrane potential over the next 30sec. Subthreshold and suprathreshold membrane responses in current clampwere elicited by injecting −200 to +400 pA in 50 pA increments (baselineVm was maintained at −70 mV, by injecting the required current, ifnecessary). Sag was measured during the −200 pA current injection, usingthe formula, SAG=(V_(min)−V_(steady-state))/V_(steady-state). The firstresulting action potential (AP) at rheobase was analyzed for AP width.AP width was calculated as the full-width at the half-maximum amplitudeof the AP.

Both slice electrophysiology experiments utilized borosilicate pipettes(World Precision Instruments) pulled into patch electrodes with 2.5-6 MΩresistance (Sutter Instruments) and filled with a potassium-basedintracellular solution, which was composed of the following (in mM): 128K-gluconate, 10 HEPES, 4 MgCl₂, 4 Na₂ATP, 0.3 Tris-GTP, 10 Trisphosphocreatine, 1 EGTA, and 3 sodium ascorbate (pH=7.25, 295 mOsm).Normality of the data collected was confirmed via Shapiro-Wilk test.

Western Blot. Co-immunoprecipitation of munc18 and syntaxin was carriedout using PEI transfection of HEK293 cells (American Type CultureCollection) plated and maintained in DMEM medium with 10% FBS andpenicillin/streptomycin. 24 hr prior to transfection, HEK293 cells areplated onto 150 mm petri dishes from confluent T75 flasks at the ratioof 2/3 flask per plate. 24 hr after plating, PEI transfection wascarried out by mixing 25% munc18 (OriGene RC204873), 25% syntaxin 1A(gift from Raymond A Frizzell, Children's Hospital of Pittsburgh), and50% pcDNA3 (Invitrogen) plasmids (28 pg total plasmids with 500 μlmedium without penicillin/streptomycin, and 110 μl PEI at 1 mg/ml). ThePEI was lastly added to the mixture drop-wise to avoid clumping of theDNA precipitates. This transfection reagent was allowed to incubate inroom temperature for at least 5 min. The HEK293 medium was replaced withmedium without penicillin/streptomycin prior to the addition of thetransfection mixture. At 24 hr after transfection, the transfectionmedium was replaced with regular medium containing either cpd5 or DMSO.The cells were lysed and protein was harvested 24 hr after cpd5/DMSOtreatment using 200 μl NP40 buffer (Invitrogen) containingphenylmethylsulfonyl fluoride (PMSF, Sigma-Aldrich) and proteaseinhibitor cocktail (¼ tablet, cOmplete Mini, EDTA-free, Sigma-Aldrich).The resulting HEK293 sample was immunoprecipitated using mouseanti-syntaxin 1A antibody (abeam). The western blot was probed using theBiogen system with the same syntaxin 1A antibody and mouse anti-Flag(Sigma-Aldrich) used for the detection of munc18. Quantification ofprotein pulldown was normalized to the syntaxin signal beforecomparisons. SDS-PAGE in this study are run in 10% acrylamide. Smallvariations in band separation are caused by the semi-wet transfermethod.

The compositions and methods of the appended claims are not limited inscope by the specific compositions and methods described herein, whichare intended as illustrations of a few aspects of the claims and anycompositions and methods that are functionally equivalent are intendedto fall within the scope of the claims. Various modifications of thecompositions and methods in addition to those shown and described hereinare intended to fall within the scope of the appended claims. Further,while only certain representative compositions and method stepsdisclosed herein are specifically described, other combinations of thecompositions and method steps also are intended to fall within the scopeof the appended claims, even if not specifically recited. Thus, acombination of steps, elements, components, or constituents may beexplicitly mentioned herein or less, however, other combinations ofsteps, elements, components, and constituents are included, even thoughnot explicitly stated. The term “comprising” and variations thereof asused herein is used synonymously with the term “including” andvariations thereof and are open, non-limiting terms. Although the terms“comprising” and “including” have been used herein to describe variousembodiments, the terms “consisting essentially of” and “consisting of”can be used in place of “comprising” and “including” to provide for morespecific embodiments of the invention and are also disclosed. Other thanin the examples, or where otherwise noted, all numbers expressingquantities of ingredients, reaction conditions, and so forth used in thespecification and claims are to be understood at the very least, and notas an attempt to limit the application of the doctrine of equivalents tothe scope of the claims, to be construed in light of the number ofsignificant digits and ordinary rounding approaches.

1. A method of treating a neurological condition, comprisingadministering a pharmaceutical composition comprising a compound ofFormula (I):

or a pharmaceutically acceptable salt thereof, wherein Ar¹ and Ar² areindependently aryl and heteroaryl groups; L¹ and L² are optionallypresent linking groups; Q¹ is absent, or a group having the formula—CR^(q1)R^(q1′)—; wherein R^(q1) is selected from R^(q1a), OR^(q1a),N(R^(q1a))₂, SO₂R^(q1a), SO₂N(R^(q1a))₂, C(O)R^(q1a); C(O)OR^(q1a),OC(O)R^(q1a); C(O)N(R^(q1a))₂, N(R^(q1a))C(O)R^(q1a), OC(O)N(R^(q1a))₂,N(R^(q1a))C(O)N(R^(q1a))₂, wherein R^(q1a) is in each case independentlyselected from hydrogen, C₁₋₈alkyl, C₂₋₈alkenyl, C₂₋₈alkynyl, aryl,C₁₋₈heteroaryl, C₃₋₈cycloalkyl, or C₁₋₈heterocyclyl; R^(q1′) is selectedfrom R^(q1′a), OR^(q1′a), N(R^(q1′a))₂, SO₂R^(q1′a), SO₂N(R^(q1′a))₂,C(O)R^(q1′a); C(O)OR^(q1′a), OC(O)R^(q1′a); C(O)N(R^(q1′a))₂,N(R^(q1′a))C(O)R^(q1′a), OC(O)N(R^(q1′a))₂, N(R^(q1′a))C(O)N(R^(q1′a))₂,wherein R^(q1′a) is in each case independently selected from hydrogen,C₁₋₈alkyl, C₂₋₈alkenyl, C₂₋₈alkynyl, aryl, C₁₋₈heteroaryl,C₃₋₈cycloalkyl, or C₁₋₈heterocyclyl; Q² is absent, or a group having theformula —CR^(q2)R^(q2′)—; wherein R^(q2) is selected from R^(q2a),OR^(q2a), N(R^(q2a))₂, SO₂R^(q2a), SO₂N(R^(q2a))₂, C(O)R^(q2a);C(O)OR^(q2a), OC(O)R^(q2a); C(O)N(R^(q2a))₂, N(R^(q2a))C(O)R^(q2a),OC(O)N(R^(q2a))₂, N(R^(q2a))C(O)N(R^(q2a))₂, wherein R^(q2a) is in eachcase independently selected from hydrogen, C₁₋₈alkyl, C₂₋₈alkenyl,C₂₋₈alkynyl, aryl, C₁₋₈heteroaryl, C₃₋₈cycloalkyl, or C₁₋₈heterocyclyl;R^(q2′) is selected from R^(q2′a), OR^(q2′a), N(R^(q2′a))₂, SO₂R^(q2′a),SO₂N(R^(q2′a))₂, C(O)R^(q2′a); C(O)OR^(q2′a), OC(O)R^(q2′a);C(O)N(R^(q2′a))₂, N(R^(q2′a))C(O)R^(q2′a), OC(O)N(R^(q2′a))₂,N(R^(q2′a))C(O)N(R^(q2′a))₂, wherein R^(q2′a) is in each caseindependently selected from hydrogen, C₁₋₈alkyl, C₂₋₈alkenyl,C₂₋₈alkynyl, aryl, C₁₋₈heteroaryl, C₃₋₈cycloalkyl, or C₁₋₈heterocyclyl;Z is O, S, or NR³; R¹ is selected from R^(1a) or OR^(1a), wherein R^(1a)is selected from hydrogen or C₁₋₈alkyl; R² is selected from R^(2a) orOR^(2a), wherein R^(2a) is selected from hydrogen or C₁₋₈alkyl; R³ isselected from R^(3a), OR^(3a), N(R^(3a))₂, SO₂R^(3a), SO₂N(R^(3a))₂,C(O)R^(3a); C(O)OR^(3a), OC(O)R^(3a); C(O)N(R^(3a))₂,N(R^(3a))C(O)R^(3a), OC(O)N(R^(3a))₂, N(R^(3a))C(O)N(R^(3a))₂, whereinR^(3a) is in each case independently selected from hydrogen, C₁₋₈alkyl,C₂₋₈alkenyl, C₂₋₈alkynyl, aryl, C₁₋₈heteroaryl, C₃₋₈cycloalkyl, orC₁₋₈heterocyclyl; wherein any of R¹, R², R³, L¹, L², Ar¹, or Ar² maytogether form a ring.
 2. The method according to claim 1, wherein Ar¹has the structure:

wherein X¹ is O, Se, Se, NR^(x), or an olefin having the formula—C(R)═C(R)—, X² is CR, or N; R^(x) is hydrogen, C₁₋₈alkyl, C₂₋₈alkenyl,C₂₋₈alkynyl, aryl, heteroaryl, C₃₋₈cycloalkyl, and C₁₋₈heteroaryl; R isin each case independently selected from R^(a), OR^(a), N(R^(a))₂,SR^(a), SO₂R^(a), SO₂N(R^(a))₂, C(O)R^(a); C(O)OR^(a), OC(O)R^(a);C(O)N(R^(a))₂, N(R^(a))C(O)R^(a), OC(O)N(R^(a))₂, N(R^(a))C(O)N(R^(a))₂,wherein R^(a) is in each case independently selected from hydrogen,C₁₋₈alkyl, C₂₋₈alkenyl, C₂₋₈alkynyl, aryl, C₁₋₈heteroaryl,C₃₋₈cycloalkyl, or C₁₋₈heterocyclyl; wherein any two or more of R,R^(a), R^(x), L¹ or R¹ may together form a ring.
 3. The method accordingto claim 1, wherein Ar¹ has the structure:

R is in each case independently selected from R^(a), OR^(a), N(R^(a))₂,SR^(a), SO₂R^(a), SO₂N(R^(a))₂, C(O)R^(a); C(O)OR^(a), OC(O)R^(a);C(O)N(R^(a))₂, N(R^(a))C(O)R^(a), OC(O)N(R^(a))₂, N(R^(a))C(O)N(R^(a))₂,wherein R^(a) is in each case independently selected from hydrogen,C₁₋₈alkyl, C₂₋₈alkenyl, C₂₋₈alkynyl, aryl, C₁₋₈heteroaryl,C₃₋₈cycloalkyl, or C₁₋₈heterocyclyl; wherein any two or more of R,R^(a), R^(x), L¹ or R¹ may together form a ring.
 4. (canceled)
 5. Themethod according to claim 1, wherein Ar¹ has the structure:

wherein, R⁵ is selected from R^(5a), OR^(5a), N(R^(5a))₂, SiR^(5a) ₃,SR^(5a), SO₂R^(5a), SO₂N(R^(5a))₂, C(O)R^(5a); C(O)OR^(5a), OC(O)R^(5a);C(O)N(R^(5a))₂, N(R^(5a))C(O)R^(5a), OC(O)N(R^(5a))₂,N(R^(5a))C(O)N(R^(5a))₂, F, Cl, Br, I, cyano, and nitro, wherein R^(5a)is in each case independently selected from hydrogen, C₁₋₈alkyl,C₂₋₈alkenyl, C₂₋₈alkynyl, aryl, C₁₋₈heteroaryl, C₃₋₈cycloalkyl, orC₁₋₈heterocyclyl; R⁶ is selected from R^(6a), OR^(6a), N(R^(6a))₂,SiR^(6a) ₃, SR^(6a), SO₂R^(6a), SO₂N(R^(6a))₂, C(O)R^(6a); C(O)OR^(6a),OC(O)R^(6a); C(O)N(R^(6a))₂, N(R^(6a))C(O)R^(6a), OC(O)N(R^(6a))₂,N(R^(6a))C(O)N(R^(6a))₂, F, Cl, Br, I, cyano, and nitro, wherein R^(6a)is in each case independently selected from hydrogen, C₁₋₈alkyl,C₂₋₈alkenyl, C₂₋₈alkynyl, aryl, C₁₋₈heteroaryl, C₃₋₈cycloalkyl, orC₁₋₈heterocyclyl; R⁷ is selected from R^(7a), OR^(7a), N(R^(7a))₂,SiR^(7a) ₃, SR^(7a), SO₂R^(7a), SO₂N(R^(7a))₂, C(O)R^(7a); C(O)OR^(7a),OC(O)R^(7a); C(O)N(R^(7a))₂, N(R^(7a))C(O)R^(7a), OC(O)N(R^(7a))₂,N(R^(7a))C(O)N(R^(7a))₂, F, Cl, Br, I, cyano, and nitro, wherein R^(7a)is in each case independently selected from hydrogen, C₁₋₈alkyl,C₂₋₈alkenyl, C₂₋₈alkynyl, aryl, C₁₋₈heteroaryl, C₃₋₈cycloalkyl, orC₁₋₈heterocyclyl; R⁸ is selected from R^(8a), OR^(8a), N(R^(8a))₂,SiR^(8a) ₃, SR^(8a), SO₂R^(8a), SO₂N(R^(8a))₂, C(O)R^(8a); C(O)OR^(8a),OC(O)R^(8a); C(O)N(R^(8a))₂, N(R^(8a))C(O)R^(8a), OC(O)N(R^(8a))₂,N(R^(8a))C(O)N(R^(8a))₂, F, Cl, Br, I, cyano, and nitro, wherein R^(8a)is in each case independently selected from hydrogen, C₁₋₈alkyl,C₂₋₈alkenyl, C₂₋₈alkynyl, aryl, C₁₋₈heteroaryl, C₃₋₈cycloalkyl, orC₁₋₈heterocyclyl; R⁹ is selected from R^(9a), OR^(9a), N(R^(9a))₂,SiR^(9a) ₃, SR^(9a), SO₂R^(9a), SO₂N(R^(9a))₂, C(O)R^(9a); C(O)OR^(9a),OC(O)R^(9a); C(O)N(R^(9a))₂, N(R^(9a))C(O)R^(9a), OC(O)N(R^(9a))₂,N(R^(9a))C(O)N(R^(9a))₂, F, Cl, Br, I, cyano, and nitro, wherein R^(9a)is in each case independently selected from hydrogen, C₁₋₈alkyl,C₂₋₈alkenyl, C₂₋₈alkynyl, aryl, C₁₋₈heteroaryl, C₃₋₈cycloalkyl, orC₁₋₈heterocyclyl; wherein any two or more of L¹, R¹, R⁵, R⁶, R⁷, R⁸, andR⁹ may together form a ring. 6-15. (canceled)
 16. The method accordingto claim 1, wherein, R⁵ is selected from R^(5a), OR^(5a), N(R^(5a))₂,SiR^(5a) ₃, SR^(5a), SO₂R^(5a), SO₂N(R^(5a))₂, C(O)R^(5a); C(O)OR^(5a),OC(O)R^(5a); C(O)N(R^(5a))₂, N(R^(5a))C(O)R^(5a), OC(O)N(R^(5a))₂,N(R^(5a))C(O)N(R^(5a))₂, F, Cl, Br, I, cyano, and nitro, wherein R^(5a)is in each case independently selected from hydrogen, C₁₋₈alkyl,C₂₋₈alkenyl, C₂₋₈alkynyl, aryl, C₁₋₈heteroaryl, C₃₋₈cycloalkyl, orC₁₋₈heterocyclyl; R⁶ is selected from R^(6a), OR^(6a), N(R^(6a))₂,SiR^(6a) ₃, SR^(6a), SO₂R^(6a), SO₂N(R^(6a))₂, C(O)R^(6a); C(O)OR^(6a),OC(O)R^(6a); C(O)N(R^(6a))₂, N(R^(6a))C(O)R^(6a), OC(O)N(R^(6a))₂,N(R^(6a))C(O)N(R^(6a))₂, F, Cl, Br, I, cyano, and nitro, wherein R^(6a)is in each case independently selected from hydrogen, C₁₋₈alkyl,C₂₋₈alkenyl, C₂₋₈alkynyl, aryl, C₁₋₈heteroaryl, C₃₋₈cycloalkyl, orC₁₋₈heterocyclyl; R⁷, R⁸, and R⁹ are each hydrogen, and wherein any twoor more of L¹, R¹, R⁵, and R⁶ may together form a ring. 17-21.(canceled)
 22. The method according to claim 16, wherein R⁵ is selectedfrom C₁₋₄alkyl, C₁₋₄haloalkyl, C₁₋₄alkoxy, or C₁₋₄haloalkoxy, and R⁶ isselected from C₁₋₄alkyl, C₁₋₄haloalkyl, C₁₋₄alkoxy, or C₁₋₄haloalkoxy.23-35. (canceled)
 36. The method according to claim 1, wherein L¹ is agroup having the formula —(CR⁴R^(4′))_(n)—, wherein: n is from 0-8; R⁴is in each case independently selected from R^(4a), OR^(4a), N(R^(4a))₂,SiR^(4a) ₃, SR^(4a), SO₂R^(4a), SO₂N(R^(4a))₂, C(O)R^(4a); C(O)OR^(4a),OC(O)R^(4a); C(O)N(R^(4a))₂, N(R^(4a))C(O)R^(4a), OC(O)N(R^(4a))₂,N(R^(4a))C(O)N(R^(4a))₂, F, Cl, Br, I, cyano, and nitro, wherein R^(4a)is in each case independently selected from hydrogen, C₁₋₈alkyl,C₂₋₈alkenyl, C₂₋₈alkynyl, aryl, C₁₋₈heteroaryl, C₃₋₈cycloalkyl, orC₁₋₈heterocyclyl; R^(4′) is in each case independently selected fromR^(4′a), OR^(4′a), N(R^(4′a))₂, SiR^(4′a) ₃, SR^(4′a), SO₂R^(4′a),SO₂N(R^(4′a))₂, C(O)R^(4′a); C(O)OR^(4′a), OC(O)R^(4′a);C(O)N(R^(4′a))₂, N(R^(4′a))C(O)R^(4′a), OC(O)N(R^(4′a))₂,N(R^(4′a))C(O)N(R^(4′a))₂, F, Cl, Br, I, cyano, and nitro, whereinR^(4′a) is in each case independently selected from hydrogen, C₁₋₈alkyl,C₂₋₈alkenyl, C₂₋₈alkynyl, aryl, C₁₋₈heteroaryl, C₃₋₈cycloalkyl, orC₁₋₈heterocyclyl; wherein any two of R⁴ and R^(4′) may together form acarbonyl, imine, double bond, or triple bond; and wherein any two ormore of R¹, R³, R⁴, R^(4′), R⁵, R⁶, R⁷, R⁸, and R⁹ may together form aring.
 37. The method according to claim 36, wherein L¹ is a group havingthe formula —(CR⁴R^(4′))_(n)—, wherein n is from 0-8, and R⁴ and R^(4′)are in each case hydrogen.
 38. (canceled)
 39. The method according toclaim 1, wherein L² is a group having the formula —(CR¹⁰R^(10′))_(n′)—,wherein: n′ is from 0-8; R¹⁰ is in each case independently selected fromR^(10a), OR^(10a), N(R^(10a))₂, SiR^(10a) ₃, SR^(10a), SO₂R^(10a),SO₂N(R^(10a))₂, C(O)R^(10a); C(O)OR^(10a), OC(O)R^(10a);C(O)N(R^(10a))₂, N(R^(10a))C(O)R^(10a), OC(O)N(R^(10a))₂,N(R^(10a))C(O)N(R^(10a))₂, F, Cl, Br, I, cyano, and nitro, whereinR^(10a) is in each case independently selected from hydrogen, C₁₋₈alkyl,C₂₋₈alkenyl, C₂₋₈alkynyl, aryl, C₁₋₈heteroaryl, C₃₋₈cycloalkyl, orC₁₋₈heterocyclyl; R^(10′) is in each case independently selected fromR^(10′a), OR^(10′a), N(R^(10′a))₂, SiR^(10′a) ₃, SR^(10′a), SO₂R^(10′a),SO₂N(R^(10′a))₂, C(O)R^(10′a); C(O)OR^(10′a), OC(O)R^(10′a);C(O)N(R^(10′a))₂, N(R^(10′a))C(O)R^(10′a), OC(O)N(R^(10′a))₂,N(R^(10′a))C(O)N(R^(10′a))₂, F, Cl, Br, I, cyano, and nitro, whereinR^(10′a) is in each case independently selected from hydrogen,C₁₋₈alkyl, C₂₋₈alkenyl, C₂₋₈alkynyl, aryl, C₁₋₈heteroaryl,C₃₋₈cycloalkyl, or C₁₋₈heterocyclyl; wherein any two of R¹⁰ and R^(10′)may together form a carbonyl, imine, double bond or triple bond; andwherein any two or more of R¹, R³, Ar², R¹⁰, and R^(10′) may togetherform a ring.
 40. The method according to claim 1, wherein L² is absent.41. The method according to claim 1, wherein Ar² has the formula:

wherein X¹ is O, Se, Se, NR^(x), or an olefin having the formula—C(R)═C(R)—, X² is CR, or N; R^(x) is hydrogen, C₁₋₈alkyl, C₂₋₈alkenyl,C₂₋₈alkynyl, aryl, heteroaryl, C₃₋₈cycloalkyl, and C₁₋₈heteroaryl; R isin each case independently selected from R^(a), OR^(a), N(R^(a))₂,SR^(a), SO₂R^(a), SO₂N(R^(a))₂, C(O)R^(a); C(O)OR^(a), OC(O)R^(a);C(O)N(R^(a))₂, N(R^(a))C(O)R^(a), OC(O)N(R^(a))₂, N(R^(a))C(O)N(R^(a))₂,wherein R^(a) is in each case independently selected from hydrogen,C₁₋₈alkyl, C₂₋₈alkenyl, C₂₋₈alkynyl, aryl, C₁₋₈heteroaryl,C₃₋₈cycloalkyl, or C₁₋₈heterocyclyl; wherein any two or more of R,R^(a), R^(x), L¹ or R¹ may together form a ring.
 42. The methodaccording to claim 1, wherein Ar² has the structure:

R is in each case independently selected from R^(a), OR^(a), N(R^(a))₂,SR^(a), SO₂R^(a), SO₂N(R^(a))₂, C(O)R^(a); C(O)OR^(a), OC(O)R^(a);C(O)N(R^(a))₂, N(R^(a))C(O)R^(a), OC(O)N(R^(a))₂, N(R^(a))C(O)N(R^(a))₂,wherein R^(a) is in each case independently selected from hydrogen,C₁₋₈alkyl, C₂₋₈alkenyl, C₂₋₈alkynyl, aryl, C₁₋₈heteroaryl,C₃₋₈cycloalkyl, or C₁₋₈heterocyclyl; wherein any two or more of R,R^(a), R^(x), L² or R¹ may together form a ring.
 43. (canceled)
 44. Themethod according to claim 1, wherein Ar² has the formula:

wherein R¹⁰ is selected from R^(10a), OR^(10a), N(R^(10a))₂, SiR^(10a)₃, SR^(10a), SO₂R^(10a), SO₂N(R^(10a))₂, C(O)R^(10a); C(O)OR^(10a),OC(O)R^(10a); C(O)N(R^(10a))₂, N(R^(10a))C(O)R^(10a), OC(O)N(R^(10a))₂,N(R^(10a))C(O)N(R^(10a))₂, F, Cl, Br, I, cyano, and nitro, whereinR^(10a) is in each case independently selected from hydrogen,C_(1-13a)lkyl, C_(2-13a)lkenyl, C_(2-13a)lkynyl, aryl, C₁₋₈heteroaryl,C₃₋₈cycloalkyl, or C₁₋₈heterocyclyl; R¹¹ is selected from R^(11a),OR^(11a), N(R^(11a))₂, SiR^(11a) ₃, SR^(11a), SO₂R^(11a),SO₂N(R^(11a))₂, C(O)R^(11a); C(O)OR^(11a), OC(O)R^(11a);C(O)N(R^(11a))₂, N(R^(11a))C(O)R^(11a), OC(O)N(R^(11a))₂,N(R^(11a))C(O)N(R^(11a))₂, F, Cl, Br, I, cyano, and nitro, whereinR^(11a) is in each case independently selected from hydrogen,C_(1-13a)lkyl, C_(2-13a)lkenyl, C_(2-13a)lkynyl, aryl, C₁₋₈heteroaryl,C₃₋₈cycloalkyl, or C₁₋₈heterocyclyl; R¹² is selected from R^(12a),OR^(12a), N(R^(12a))₂, SiR^(12a) ₃, SR^(12a), SO₂R^(12a),SO₂N(R^(12a))₂, C(O)R^(12a); C(O)OR^(12a), OC(O)R^(12a);C(O)N(R^(12a))₂, N(R^(12a))C(O)R^(12a), OC(O)N(R^(12a))₂,N(R^(12a))C(O)N(R^(12a))₂, F, Cl, Br, I, cyano, and nitro, whereinR^(12a) is in each case independently selected from hydrogen,C_(1-13a)lkyl, C_(2-13a)lkenyl, C_(2-13a)lkynyl, aryl, C₁₋₈heteroaryl,C₃₋₈cycloalkyl, or C₁₋₈heterocyclyl; R¹³ is selected from R^(13a),OR^(13a), N(R^(13a))₂, SiR^(13a) ₃, SR^(13a), SO₂R^(13a),SO₂N(R^(13a))₂, C(O)R^(13a); C(O)OR^(13a), OC(O)R^(13a);C(O)N(R^(13a))₂, N(R^(13a))C(O)R^(13a), OC(O)N(R^(13a))₂,N(R^(13a))C(O)N(R^(13a))₂, F, Cl, Br, I, cyano, and nitro, whereinR^(13a) is in each case independently selected from hydrogen,C_(1-13a)lkyl, C_(2-13a)lkenyl, C_(2-13a)lkynyl, aryl, C₁₋₈heteroaryl,C₃₋₈cycloalkyl, or C₁₋₈heterocyclyl; R¹⁴ is selected from R^(14a),OR^(14a), N(R^(14a))₂, SiR^(14a) ₃, SR^(14a), SO₂R^(14a),SO₂N(R^(14a))₂, C(O)R^(14a); C(O)OR^(14a), OC(O)R^(14a);C(O)N(R^(14a))₂, N(R^(14a))C(O)R^(14a), OC(O)N(R^(14a))₂,N(R^(14a))C(O)N(R^(14a))₂, F, Cl, Br, I, cyano, and nitro, whereinR^(14a) is in each case independently selected from hydrogen,C_(1-13a)lkyl, C_(2-13a)lkenyl, C_(2-13a)lkynyl, aryl, C₁₋₈heteroaryl,C₃₋₈cycloalkyl, or C₁₋₈heterocyclyl; wherein any two or more of L¹, R¹,R¹⁰, R¹¹, R¹², R¹³, and R¹⁴ may together form a ring. 45-61. (canceled)62. The method according to claim 44, wherein R¹¹ is a group having theformula:

wherein X¹ is O, Se, Se, NR^(x), or an olefin having the formula—C(R)═C(R)—, X² is CR, or N; R^(x) is hydrogen, C₁₋₈alkyl, C₂₋₈alkenyl,C₂₋₈alkynyl, aryl, heteroaryl, C₃₋₈cycloalkyl, and C₁₋₈heteroaryl; R^(y)is in each case independently selected from R^(ya), OR^(ya), N(R^(ya))₂,SR^(ya), SO₂R^(ya), SO₂N(R^(ya))₂, C(O)R^(ya); C(O)OR^(ya), OC(O)R^(ya);C(O)N(R^(ya))₂, N(R^(ya))C(O)R^(ya), OC(O)N(R^(ya))₂,N(R^(ya))C(O)N(R^(ya))₂, wherein R^(ya) is in each case independentlyselected from hydrogen, C₁₋₈alkyl, C₂₋₈alkenyl, C₂₋₈alkynyl, aryl,C₁₋₈heteroaryl, C₃₋₈cycloalkyl, or C₁₋₈heterocyclyl; wherein any two ormore of R, R^(ya), R^(x), R³, L² or R² may together form a ring. 63-65.(canceled)
 66. The method according to claim 62, wherein R¹¹ is anoptionally substituted ring system having the formula:


67. The method according to claim 1, wherein R¹ and R² are eachhydrogen, and Z is oxygen. 68-72. (canceled)
 73. The method according toclaim 1, wherein the neurological condition comprising aneurodegenerative disease.
 74. The method according to claim 73, whereinthe neurodegenerative disease comprises Alzheimer's disease, Parkinson'sdisease, Huntington's disease, ALS, multiple sclerosis, Lewy bodydementia, vascular dementia, progressive supranuclear palsy,corticobasal degeneration, multiple system atrophy and frontotemporaldementia.
 75. The method according to claim 1, wherein the neurologicaldisorder comprises a neurological injury.
 76. The method according toclaim 75, wherein the neurological injury comprises cerebral ischemia,stroke, CNS trauma/injury, traumatic brain injury, or any othercondition associated with neuronal damage and/or neuronal cell death.77-78. (canceled)